Is DIRAS3 p.Gln76Ter (c.226C>T) pathogenic?

DIRAS3 p.Gln76Ter (c.226C>T) is classified Uncertain significance in DIRAS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-07). Very rare (popmax 0.000657%).

How common is DIRAS3 p.Gln76Ter (c.226C>T) in the general population?

DIRAS3 p.Gln76Ter (c.226C>T) is very rare (popmax 0.000657%) (gnomAD).

DIRAS3 p.Gln76Ter

c.226C>T · VCV4893934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000657%)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.5, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000657%

Overall 0.000657% 1/152,188 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.Gln76Ter
Coding: c.226C>T
MANE Select: NM_004675
Type: single nucleotide variant
Location: chr1:68047072 (GRCh38)
Gene constraint: LOEUF 1.84 · pLI 0.34 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.19 · 1 PDB

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-gln76ter (accessed [today's date]).

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