Is TP73 p.Ala2Ser (c.4G>T) pathogenic?

TP73 p.Ala2Ser (c.4G>T) is classified Likely benign in TP73 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.0572); Ultra-rare (popmax 0.0226%, amr); Associated with Inborn genetic diseases.

What condition is associated with TP73 p.Ala2Ser (c.4G>T)?

TP73 p.Ala2Ser (c.4G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TP73 p.Ala2Ser (c.4G>T) in the general population?

TP73 p.Ala2Ser (c.4G>T) is ultra-rare (popmax 0.0226%, amr) (gnomAD).

What do computational predictors say about TP73 p.Ala2Ser (c.4G>T)?

AlphaMissense predicts likely benign (score 0.0572) — an in-silico prediction, not a clinical call.

TP73 p.Ala2Ser

c.4G>T · rs745657321 · VCV2216015

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0572 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0572	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -5.94	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 3.1	GERP 0.75, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 40 kb · p 0.3 · regional, not allelic
Overall
CADD	13.46	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 0.0226% Admixed American · 12/53,114 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.000904% 14/1,548,446 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0226%	4,426
African / African-American	0.00273%	36,641

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: TP73
Protein: p.Ala2Ser
Coding: c.4G>T
MANE Select: NM_005427
dbSNP: rs745657321
Type: single nucleotide variant
Location: chr1:3682369 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI 0.29 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.25 · 28 PDB
Residue 2: the 'transactivation' region

Full TP73 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TP73 p.Gly451Arg Uncertain significance ★★ ⚠ same condition
TP73 p.Ala100Thr Uncertain significance ★ ⚠ same condition
TP73 p.Ala112Val Uncertain significance ★ ⚠ same condition
TP73 p.Ala156Thr Uncertain significance ★ ⚠ same condition
TP73 p.Ala320Thr Uncertain significance ★ ⚠ same condition
TP73 p.Ala441Pro Uncertain significance ★ ⚠ same condition
TP73 p.Ala441Thr Uncertain significance ★ ⚠ same condition
TP73 p.Ala459Val Uncertain significance ★ ⚠ 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/tp73-p-ala2ser (accessed [today's date]).

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