Is DHX57 p.Ala1014Pro (c.3040G>C) pathogenic?

DHX57 p.Ala1014Pro (c.3040G>C) is classified Likely benign in DHX57 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-04-21). AlphaMissense: likely benign (0.1381); Rare (popmax 0.431%, afr); Associated with DHX57-related disorder.

What condition is associated with DHX57 p.Ala1014Pro (c.3040G>C)?

DHX57 p.Ala1014Pro (c.3040G>C) is associated with DHX57-related disorder (ClinVar).

How common is DHX57 p.Ala1014Pro (c.3040G>C) in the general population?

DHX57 p.Ala1014Pro (c.3040G>C) is rare (popmax 0.431%, afr) (gnomAD).

What do computational predictors say about DHX57 p.Ala1014Pro (c.3040G>C)?

AlphaMissense predicts likely benign (score 0.1381) — an in-silico prediction, not a clinical call.

DHX57 p.Ala1014Pro

c.3040G>C · rs142332924 · VCV3037682

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1381 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.431%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DHX57-related disorder

Computational evidence

Protein change
AlphaMissense	0.1381	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -9.02	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 -2	GERP -5.2
Regional constraint	o/e 1.11	unconstrained · MANE · 70 kb · p 5.6e-06 · regional, not allelic
Overall
CADD	1.587	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 0.431% African / African-American · 323/74,922 alleles

Filtering AF 0.392% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.377%

Overall 0.0236% 381/1,612,556 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.431%	232
Admixed American	0.0452%	2,214
Remaining individualsnot grpmax-eligible	0.0336%	2,974
South Asian	0.0011%	90,900
European (non-Finnish)	0.000763%	131,010

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: DHX57
Protein: p.Ala1014Pro
Coding: c.3040G>C
MANE Select: NM_198963
dbSNP: rs142332924
Type: single nucleotide variant
Location: chr2:38823244 (GRCh38)
Gene constraint: LOEUF 0.742 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.68

Full DHX57 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DHX57-related disorder

Similar variants

DHX57 p.Ala1014Val Uncertain significance ★ ⚠ same residue
DHX57 p.Arg612His Likely benign same condition
DHX57 p.Phe1097Leu Likely benign same condition
DHX57 p.Phe952Leu Likely benign same condition
DHX57 p.Pro159Ser Likely benign same condition
DHX57 p.Ala1084Thr Uncertain significance ★ ⚠ same type
DHX57 p.Ala1115Val Uncertain significance ★ ⚠ same type
DHX57 p.Ala1117Gly 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/dhx57-p-ala1014pro (accessed [today's date]).

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