Is DHX33 p.Val431Met (c.1291G>A) pathogenic?

DHX33 p.Val431Met (c.1291G>A) is classified Uncertain significance in DHX33 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely benign (0.1308); Ultra-rare (popmax 0.0517%, amr).

How common is DHX33 p.Val431Met (c.1291G>A) in the general population?

DHX33 p.Val431Met (c.1291G>A) is ultra-rare (popmax 0.0517%, amr) (gnomAD).

What do computational predictors say about DHX33 p.Val431Met (c.1291G>A)?

AlphaMissense predicts likely benign (score 0.1308) — an in-silico prediction, not a clinical call.

DHX33 p.Val431Met

c.1291G>A · rs143592214 · VCV2355349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1308 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0517%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1308	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -10.11	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.34	phastCons 0.12
Regional constraint	o/e 0.92	unconstrained · MANE · 25 kb · p 0.013 · regional, not allelic
Overall
CADD	20.6	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 0.0517% Admixed American · 31/60,012 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.0138% 222/1,613,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0517%	1,936
Middle Eastern	0.033%	3,030
European (non-Finnish)	0.0142%	7,065
Remaining individualsnot grpmax-eligible	0.0128%	7,813
South Asian	0.00879%	11,380
African / African-American	0.00533%	18,758
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,578
East Asian	0.00223%	44,886

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: DHX33
Protein: p.Val431Met
Coding: c.1291G>A
MANE Select: NM_020162
dbSNP: rs143592214
Type: single nucleotide variant
Location: chr17:5453837 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.90
Residue 431: the helicase c-terminal domain

Full DHX33 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DHX33 p.Ala343Ser Uncertain significance ★ ⚠ same type
DHX33 p.Ala399Gly Uncertain significance ★ ⚠ same type
DHX33 p.Ala448Thr Uncertain significance ★ ⚠ same type
DHX33 p.Ala470Val Uncertain significance ★ ⚠ same type
DHX33 p.Ala473Thr Uncertain significance ★ ⚠ same type
DHX33 p.Ala507Ser Uncertain significance ★ ⚠ same type
DHX33 p.Ala633Thr Uncertain significance ★ ⚠ same type
DHX33 p.Ala694Ser 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/dhx33-p-val431met (accessed [today's date]).

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