Is TP53 p.Asp49His (c.145G>C) pathogenic?

TP53 p.Asp49His (c.145G>C) is classified Benign in TP53 (ClinVar, Expert panel, 11 submitters; last evaluated 2025-01-16). AlphaMissense: likely benign (0.1274); Rare (popmax 0.1%, eas); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 p.Asp49His (c.145G>C)?

TP53 p.Asp49His (c.145G>C) is associated with Li-Fraumeni syndrome, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Asp49His (c.145G>C) in the general population?

TP53 p.Asp49His (c.145G>C) is rare (popmax 0.1%, eas) (gnomAD).

How is Li-Fraumeni syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TP53 p.Asp49His (c.145G>C)?

AlphaMissense predicts likely benign (score 0.1274) — an in-silico prediction, not a clinical call.

TP53 p.Asp49His

c.145G>C · rs587780728 · VCV135948

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1274 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.1%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Li-Fraumeni syndrome

ClinGen expert panel — TP53 VCEP

Benign for Li-Fraumeni syndrome. Applied ACMG criteria (verbatim):

BS1 BS2_Supporting BP4_Moderate

Curation rationale (ClinGen, verbatim)

The NM_000546.6: c.145G>C variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by histidine at amino acid 49 (p.Asp49His). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributors). The filtering allele frequency is 0.0007696 in the East Asian population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644, 15489903, 12901974, 18199664). Computational predictor scores (BayesDel = -0.0307; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). This variant has been reported as a putative founder variant in the Japanese population (PMID: 27545002). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, BS1, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.1.0; 1/16/2025)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1274	likely benign
REVEL	0.315	indeterminate
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.97, phastCons 0.004
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	8.201	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.1% East Asian · 45/44,902 alleles

Filtering AF 0.077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0688%

Overall 0.00297% 48/1,613,988 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.1%	998
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	8.47e-05%	1,180,038

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TP53
Protein: p.Asp49His
Coding: c.145G>C
MANE Select: NM_000546
dbSNP: rs587780728
Type: single nucleotide variant
Location: chr17:7676224 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 49: a UniProt-annotated variant site (in sporadic cancers; somatic mutation); a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); an α-helix; the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region

Full TP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome

For Li-Fraumeni syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

TP53 p.Asp49Asn Benign ★★★ same residue
TP53 p.Asp49= Benign/Likely benign ★★ same residue
TP53 p.Asp49Glu Uncertain significance ★ ⚠ same residue
TP53 p.Asp49Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 c.375+5G>A Likely pathogenic ★★★ same condition
TP53 c.919+1G>A Pathogenic ★★★ same condition
TP53 c.97-1G>A Pathogenic ★★★ same condition
TP53 p.Ala138Pro Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tp53-p-asp49his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown