Is SAMD9 p.Phe313Leu (c.937T>C) pathogenic?

SAMD9 p.Phe313Leu (c.937T>C) is classified Uncertain significance in SAMD9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.6476); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with SAMD9 p.Phe313Leu (c.937T>C)?

SAMD9 p.Phe313Leu (c.937T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SAMD9 p.Phe313Leu (c.937T>C) in the general population?

SAMD9 p.Phe313Leu (c.937T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SAMD9 p.Phe313Leu (c.937T>C)?

AlphaMissense predicts likely pathogenic (score 0.6476) — an in-silico prediction, not a clinical call.

SAMD9 p.Phe313Leu

c.937T>C · VCV3367672

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6476	likely pathogenic
REVEL	0.028	moderately benign-leaning
SaProt	LLR -4.65	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.26	GERP -2.4
Regional constraint	o/e 1.09	unconstrained · MANE · 1,176 bp · p 0.058 · regional, not allelic
Overall
CADD	6.481	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 0.00223% East Asian · 1/44,854 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,678 alleles · very rare exomes 7/1,461,418 · genomes 0/152,260 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,854
European (non-Finnish)	0.000509%	196,637

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.Phe313Leu
Coding: c.937T>C
MANE Select: NM_017654
Type: single nucleotide variant
Location: chr7:93105161 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB
Residue 313: a turn

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.Phe313Cys Uncertain significance ★ ⚠ same residue
SAMD9 p.Phe313= Likely benign ★ 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-phe313leu (accessed [today's date]).

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