Is DIS3 p.Gly40Val (c.119G>T) pathogenic?

DIS3 p.Gly40Val (c.119G>T) is classified Uncertain significance in DIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: likely benign (0.0966); Ultra-rare (popmax 0.0189%, afr).

How common is DIS3 p.Gly40Val (c.119G>T) in the general population?

DIS3 p.Gly40Val (c.119G>T) is ultra-rare (popmax 0.0189%, afr) (gnomAD).

What do computational predictors say about DIS3 p.Gly40Val (c.119G>T)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

DIS3 p.Gly40Val

c.119G>T · rs565866518 · VCV2372234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0189%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -7.58	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 0.75	GERP -1.4, phastCons 0.13
Regional constraint	o/e 1.09	unconstrained · MANE · 3,601 bp · p 0.15 · regional, not allelic
Overall
CADD	13.99	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 0.0189% African / African-American · 14/74,070 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00914%

Overall 0.00102% 16/1,574,620 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0189%	5,291
Remaining individualsnot grpmax-eligible	0.00328%	30,474

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: DIS3
Protein: p.Gly40Val
Coding: c.119G>T
MANE Select: NM_014953
dbSNP: rs565866518
Type: single nucleotide variant
Location: chr13:72781714 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 3 PDB

Full DIS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIS3 p.Ala518Thr Uncertain significance ★★ ⚠ same type
DIS3 p.Ala401Val Benign ★★ ⚠ same type
DIS3 p.Ter959Gln Likely benign ★★ same type
PIBF1 p.Ile51Val Benign/Likely benign ★★ same type
PIBF1 p.Met73Thr Benign/Likely benign ★★ same type
DIS3 p.Arg638Ter Likely pathogenic ★ same type
DIS3 c.228+3G>A Uncertain significance ★ same type
DIS3 c.2511+1G>C 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/dis3-p-gly40val (accessed [today's date]).

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