Is SAMD9 p.Phe342Ser (c.1025T>C) pathogenic?

SAMD9 p.Phe342Ser (c.1025T>C) is classified Uncertain significance in SAMD9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-16). AlphaMissense: likely pathogenic (0.7795); Very rare (popmax 0.00288%, nfe).

How common is SAMD9 p.Phe342Ser (c.1025T>C) in the general population?

SAMD9 p.Phe342Ser (c.1025T>C) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about SAMD9 p.Phe342Ser (c.1025T>C)?

AlphaMissense predicts likely pathogenic (score 0.7795) — an in-silico prediction, not a clinical call.

SAMD9 p.Phe342Ser

c.1025T>C · rs769654702 · VCV1901149

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7795	likely pathogenic · top 10% in SAMD9
REVEL	0.267	benign-leaning
SaProt	LLR -11.36	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 4.2, phastCons 0.94
Regional constraint	o/e 1.09	unconstrained · MANE · 1,176 bp · p 0.058 · regional, not allelic
Overall
CADD	21.3	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 0.00288% European (non-Finnish) · 34/1,179,966 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00217% 35/1,613,860 alleles · very rare exomes 34/1,461,738 · genomes 1/152,122 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,705
Admixed American	0.00167%	59,988

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.Phe342Ser
Coding: c.1025T>C
MANE Select: NM_017654
dbSNP: rs769654702
Type: single nucleotide variant
Location: chr7:93105073 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB
Residue 342: a β-strand

Full SAMD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SAMD9 p.Phe342Ile Uncertain significance ★ ⚠ same residue
SAMD9 p.Phe342Leu Uncertain significance ★ ⚠ same residue
SAMD9 p.Arg1293Trp Pathogenic ★★ ⚠ same type
SAMD9 p.Arg459Gln Pathogenic ★★ ⚠ same type
SAMD9 p.Arg685Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
SAMD9 p.Arg824Gln Pathogenic ★★ ⚠ same type
SAMD9 p.Arg982Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
SAMD9 p.Arg982His Pathogenic/Likely pathogenic ★★ ⚠ same type

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-phe342ser (accessed [today's date]).

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