Is SAMD9 p.His53= (c.159T>C) pathogenic?

SAMD9 p.His53= (c.159T>C) is classified Likely benign in SAMD9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-10). Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SAMD9 p.His53= (c.159T>C)?

SAMD9 p.His53= (c.159T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SAMD9 p.His53= (c.159T>C) in the general population?

SAMD9 p.His53= (c.159T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

SAMD9 p.His53=

c.159T>C · rs759744332 · VCV3002650

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP -3.4, phastCons 0.087
Overall
CADD	1.098	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,178,990 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,611,842 alleles · very rare exomes 3/1,459,806 · genomes 2/152,036 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,560
European (non-Finnish)grpmax	0.000339%	294,748

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SAMD9
Protein: p.His53=
Coding: c.159T>C
MANE Select: NM_017654
dbSNP: rs759744332
Type: single nucleotide variant
Location: chr7:93105939 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB
Residue 53: the sam domain

Full SAMD9 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

SAMD9 p.His53Tyr Uncertain significance ★★ ⚠ same residue
SAMD9 p.His53Leu Uncertain significance ★★ ⚠ same residue
SAMD9 p.Ala1057Val Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1066Thr Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1069Thr Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1082Gly Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1102Asp Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1195Asp 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/samd9-p-his53 (accessed [today's date]).

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