Is DIRAS1 p.Ala145Ser (c.433G>T) pathogenic?

DIRAS1 p.Ala145Ser (c.433G>T) is classified Uncertain significance in DIRAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-01). AlphaMissense: likely benign (0.0848); Ultra-rare (popmax 0.0417%, amr).

How common is DIRAS1 p.Ala145Ser (c.433G>T) in the general population?

DIRAS1 p.Ala145Ser (c.433G>T) is ultra-rare (popmax 0.0417%, amr) (gnomAD).

What do computational predictors say about DIRAS1 p.Ala145Ser (c.433G>T)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

DIRAS1 p.Ala145Ser

c.433G>T · rs769610964 · VCV3082540

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 166 bp · p 0.65 · regional, not allelic
Overall
CADD	20.4	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 0.0417% Admixed American · 25/60,006 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0247%

Overall 0.00205% 33/1,608,836 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0417%	2,400
Remaining individualsnot grpmax-eligible	0.0112%	8,922
African / African-American	0.00133%	74,926

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: DIRAS1
Protein: p.Ala145Ser
Coding: c.433G>T
MANE Select: NM_145173
dbSNP: rs769610964
Type: single nucleotide variant
Location: chr19:2717374 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI 0.35 (gnomAD)
Structure: AlphaFold pLDDT 87.01 · 1 PDB
Residue 145: a β-strand

Full DIRAS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIRAS1 p.Arg181Gly Uncertain significance ★ ⚠ same type
DIRAS1 p.Arg190Gly Uncertain significance ★ ⚠ same type
DIRAS1 p.Arg190His Uncertain significance ★ ⚠ same type
DIRAS1 p.Asp113Asn Uncertain significance ★ ⚠ same type
DIRAS1 p.Asp178Glu Uncertain significance ★ ⚠ same type
DIRAS1 p.Glu41Lys Uncertain significance ★ ⚠ same type
DIRAS1 p.Gly109Ala Uncertain significance ★ ⚠ same type
DIRAS1 p.Gly79Val Uncertain significance ★ ⚠ 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/diras1-p-ala145ser (accessed [today's date]).

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