Is SAMD9 p.Ala1459Val (c.4376C>T) pathogenic?

SAMD9 p.Ala1459Val (c.4376C>T) is classified Uncertain significance in SAMD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-19). AlphaMissense: likely benign (0.1906); Very rare (popmax 0.00167%, amr).

How common is SAMD9 p.Ala1459Val (c.4376C>T) in the general population?

SAMD9 p.Ala1459Val (c.4376C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SAMD9 p.Ala1459Val (c.4376C>T)?

AlphaMissense predicts likely benign (score 0.1906) — an in-silico prediction, not a clinical call.

SAMD9 p.Ala1459Val

c.4376C>T · rs1791533456 · VCV2039292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1906 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1906	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -10.28	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 0.47, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 2,122 bp · p 6.9e-06 · regional, not allelic
Overall
CADD	17.1	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 0.00167% Admixed American · 1/59,968 alleles

Overall 0.000124% 2/1,613,602 alleles · very rare exomes 1/1,461,616 · genomes 1/151,986 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,968
European (non-Finnish)	8.48e-05%	1,179,743

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.Ala1459Val
Coding: c.4376C>T
MANE Select: NM_017654
dbSNP: rs1791533456
Type: single nucleotide variant
Location: chr7:93101722 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB

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

Similar variants

SAMD9 p.Ala1459Glu Uncertain significance ★ ⚠ same residue
SAMD9 p.Ala1459Thr Uncertain significance ★ ⚠ same residue
SAMD9 p.Ala1459= Likely benign ★ same residue
SAMD9 p.Ala1459Ser Likely benign ★ 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

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-ala1459val (accessed [today's date]).

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