Is DIRAS3 p.Lys183Glu (c.547A>G) pathogenic?

DIRAS3 p.Lys183Glu (c.547A>G) is classified Uncertain significance in DIRAS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: ambiguous (0.4105); Very rare (popmax 8.47e-05%, nfe).

How common is DIRAS3 p.Lys183Glu (c.547A>G) in the general population?

DIRAS3 p.Lys183Glu (c.547A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DIRAS3 p.Lys183Glu (c.547A>G)?

AlphaMissense predicts ambiguous (score 0.4105) — an in-silico prediction, not a clinical call.

DIRAS3 p.Lys183Glu

c.547A>G · rs2523786691 · VCV2245171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4105	ambiguous
REVEL	0.517	indeterminate
SaProt	LLR -8.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.1, phastCons 0.99
Regional constraint	o/e 0.83	unconstrained · MANE · 686 bp · p 0.0024 · regional, not allelic
Overall
CADD	19.69	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 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 6.84e-05% 1/1,461,894 alleles · very rare

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.Lys183Glu
Coding: c.547A>G
MANE Select: NM_004675
dbSNP: rs2523786691
Type: single nucleotide variant
Location: chr1:68046751 (GRCh38)
Gene constraint: LOEUF 1.84 · pLI 0.34 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.19 · 1 PDB
Residue 183: 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-lys183glu (accessed [today's date]).

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