Is DHX40 p.Pro231Ser (c.691C>T) pathogenic?

DHX40 p.Pro231Ser (c.691C>T) is classified Uncertain significance in DHX40 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-05). AlphaMissense: likely benign (0.1582); Very rare (popmax 0.00168%, amr).

How common is DHX40 p.Pro231Ser (c.691C>T) in the general population?

DHX40 p.Pro231Ser (c.691C>T) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about DHX40 p.Pro231Ser (c.691C>T)?

AlphaMissense predicts likely benign (score 0.1582) — an in-silico prediction, not a clinical call.

DHX40 p.Pro231Ser

c.691C>T · rs779351905 · VCV2216215

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1582	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -8.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 3,619 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	27.2	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 0.00168% Admixed American · 1/59,638 alleles

Overall 6.85e-05% 1/1,460,470 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: DHX40
Protein: p.Pro231Ser
Coding: c.691C>T
MANE Select: NM_024612
dbSNP: rs779351905
Type: single nucleotide variant
Location: chr17:59573884 (GRCh38)
Gene constraint: LOEUF 0.569 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 83.51
Residue 231: the helicase atp-binding domain

Full DHX40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DHX40 p.Pro231Leu Uncertain significance ★ ⚠ same residue
DHX40 p.Glu214= Benign ★★ same type
DHX40 p.Ala11Glu Uncertain significance ★ ⚠ same type
DHX40 p.Ala216Thr Uncertain significance ★ ⚠ same type
DHX40 p.Ala515Thr Uncertain significance ★ ⚠ same type
DHX40 p.Ala570Pro Uncertain significance ★ ⚠ same type
DHX40 p.Ala681Thr Uncertain significance ★ ⚠ same type
DHX40 p.Ala758Gly 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/dhx40-p-pro231ser (accessed [today's date]).

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