Is DIRAS1 p.Val191Ile (c.571G>A) pathogenic?

DIRAS1 p.Val191Ile (c.571G>A) is classified Likely benign in DIRAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). AlphaMissense: likely benign (0.0753); Very rare (popmax 0.00676%, nfe).

How common is DIRAS1 p.Val191Ile (c.571G>A) in the general population?

DIRAS1 p.Val191Ile (c.571G>A) is very rare (popmax 0.00676%, nfe) (gnomAD).

What do computational predictors say about DIRAS1 p.Val191Ile (c.571G>A)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

DIRAS1 p.Val191Ile

c.571G>A · VCV3840153

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00676%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -5.3, phastCons 0.31
Regional constraint	o/e 1.05	unconstrained · MANE · 166 bp · p 0.65 · regional, not allelic
Overall
CADD	12.15	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 0.00676% European (non-Finnish) · 79/1,168,572 alleles

Filtering AF 0.00552% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00511%

Overall 0.00507% 81/1,597,124 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00676%	14,792
Remaining individualsnot grpmax-eligible	0.00324%	30,867

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.Val191Ile
Coding: c.571G>A
MANE Select: NM_145173
Type: single nucleotide variant
Location: chr19:2717236 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI 0.35 (gnomAD)
Structure: AlphaFold pLDDT 87.01 · 1 PDB
Residue 191: the 'disordered' region

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

Similar variants

DIRAS1 p.Ala145Ser Uncertain significance ★ ⚠ same type
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

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-val191ile (accessed [today's date]).

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