Is NRAS p.Ala91Val (c.272C>T) pathogenic?

NRAS p.Ala91Val (c.272C>T) is classified Uncertain significance in NRAS (ClinVar, Expert panel, 3 submitters; last evaluated 2024-12-03). AlphaMissense: likely benign (0.1434); Very rare (popmax 0.00769%, sas); Associated with RASopathy.

What condition is associated with NRAS p.Ala91Val (c.272C>T)?

NRAS p.Ala91Val (c.272C>T) is associated with RASopathy (ClinVar).

How common is NRAS p.Ala91Val (c.272C>T) in the general population?

NRAS p.Ala91Val (c.272C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about NRAS p.Ala91Val (c.272C>T)?

AlphaMissense predicts likely benign (score 0.1434) — an in-silico prediction, not a clinical call.

NRAS p.Ala91Val

c.272C>T · rs774832953 · VCV1003866

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1434 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

ClinGen expert panel

Uncertain Significance — RASopathy VCEP (RASopathy).

Computational evidence

Protein change
AlphaMissense	0.1434	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 7,622 bp · p 6.3e-09 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,080 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.0013% 21/1,613,642 alleles · very rare exomes 20/1,461,536 · genomes 1/152,106 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,011
Admixed American	0.00333%	30,000
East Asian	0.00223%	44,888
African / African-American	0.00134%	74,882
European (non-Finnish)	0.000848%	117,970

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: NRAS
Protein: p.Ala91Val
Coding: c.272C>T
MANE Select: NM_002524
dbSNP: rs774832953
Type: single nucleotide variant
Location: chr1:114713818 (GRCh38)
Gene constraint: LOEUF 0.55 · pLI 0.94 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.56 · 36 PDB
Residue 91: an α-helix

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

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NRAS p.Ala91= Likely benign ★★ same residue
NRAS p.Ala91Gly Uncertain significance ★ ⚠ same residue
NRAS p.Gly12Ser Pathogenic ★★★ same condition
NRAS p.Gly60Glu Pathogenic ★★★ same condition
NRAS p.Ile24Asn Likely pathogenic ★★★ same condition
NRAS p.Thr50Ile Pathogenic ★★★ same condition
NRAS p.Thr58Ile Pathogenic ★★★ same condition
NRAS p.Ala11Thr 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/nras-p-ala91val (accessed [today's date]).

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