Is SAMD9 p.Val549Ala (c.1646T>C) pathogenic?

SAMD9 p.Val549Ala (c.1646T>C) is classified Uncertain significance in SAMD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: ambiguous (0.3527); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with SAMD9 p.Val549Ala (c.1646T>C)?

SAMD9 p.Val549Ala (c.1646T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SAMD9 p.Val549Ala (c.1646T>C) in the general population?

SAMD9 p.Val549Ala (c.1646T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SAMD9 p.Val549Ala (c.1646T>C)?

AlphaMissense predicts ambiguous (score 0.3527) — an in-silico prediction, not a clinical call.

SAMD9 p.Val549Ala

c.1646T>C · VCV3949524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3527 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3527	ambiguous
REVEL	0.124	moderately benign-leaning
SaProt	LLR -6.90	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	phastCons 0.99
Regional constraint	o/e 0.78	unconstrained · MANE · 1,217 bp · p 1.8e-06 · regional, not allelic
Overall
CADD	20.6	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 · 1/44,876 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,694 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
European (non-Finnish)	0.00017%	589,939

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.Val549Ala
Coding: c.1646T>C
MANE Select: NM_017654
Type: single nucleotide variant
Location: chr7:93104452 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB
Residue 549: a UniProt-annotated variant site (in)

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.Val549Met Uncertain significance ★★ ⚠ same residue
SAMD9 p.Val549Leu Benign/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-val549ala (accessed [today's date]).

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