Is DIRAS3 p.Val48Met (c.142G>A) pathogenic?

DIRAS3 p.Val48Met (c.142G>A) is classified Uncertain significance in DIRAS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-13). AlphaMissense: likely pathogenic (0.6669); Very rare (popmax 0.00223%, eas).

How common is DIRAS3 p.Val48Met (c.142G>A) in the general population?

DIRAS3 p.Val48Met (c.142G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DIRAS3 p.Val48Met (c.142G>A)?

AlphaMissense predicts likely pathogenic (score 0.6669) — an in-silico prediction, not a clinical call.

DIRAS3 p.Val48Met

c.142G>A · rs1472089567 · VCV2536683

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6669	likely pathogenic
REVEL	0.7	pathogenic-leaning
SaProt	LLR -12.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP 1.5, phastCons 0.013
Regional constraint	o/e 0.83	unconstrained · MANE · 686 bp · p 0.0024 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,890 alleles

Overall 0.000124% 2/1,614,076 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
European (non-Finnish)	8.47e-05%	1,180,050

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: DIRAS3
Protein: p.Val48Met
Coding: c.142G>A
MANE Select: NM_004675
dbSNP: rs1472089567
Type: single nucleotide variant
Location: chr1:68047156 (GRCh38)
Gene constraint: LOEUF 1.84 · pLI 0.34 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.19 · 1 PDB
Residue 48: a binding site

Full DIRAS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIRAS3 p.Ala129Thr Uncertain significance ★ ⚠ same type
DIRAS3 p.Arg18Gln Uncertain significance ★ ⚠ same type
DIRAS3 p.Arg18Trp Uncertain significance ★ ⚠ same type
DIRAS3 p.Arg27Gly Uncertain significance ★ ⚠ same type
DIRAS3 p.Arg99Leu Uncertain significance ★ ⚠ same type
DIRAS3 p.Asn174His Uncertain significance ★ ⚠ same type
DIRAS3 p.Asn217Ser Uncertain significance ★ ⚠ same type
DIRAS3 p.Gln102Arg 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/diras3-p-val48met (accessed [today's date]).

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