Is DHX35 p.Val522Ala (c.1565T>C) pathogenic?

DHX35 p.Val522Ala (c.1565T>C) is classified Uncertain significance in DHX35 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely benign (0.2078); Ultra-rare (popmax 0.0134%, eas).

How common is DHX35 p.Val522Ala (c.1565T>C) in the general population?

DHX35 p.Val522Ala (c.1565T>C) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about DHX35 p.Val522Ala (c.1565T>C)?

AlphaMissense predicts likely benign (score 0.2078) — an in-silico prediction, not a clinical call.

DHX35 p.Val522Ala

c.1565T>C · rs770232924 · VCV2349292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2078 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2078	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -8.88	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 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 76 kb · p 0.22 · regional, not allelic
Overall
CADD	23.5	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 0.0134% East Asian · 6/44,880 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000434% 7/1,614,178 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,480
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: DHX35
Protein: p.Val522Ala
Coding: c.1565T>C
MANE Select: NM_021931
dbSNP: rs770232924
Type: single nucleotide variant
Location: chr20:39021907 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.94 · 1 PDB

Full DHX35 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DHX35 p.Ala188Thr Uncertain significance ★ ⚠ same type
DHX35 p.Ala465Gly Uncertain significance ★ ⚠ same type
DHX35 p.Ala579Val Uncertain significance ★ ⚠ same type
DHX35 p.Ala671Val Uncertain significance ★ ⚠ same type
DHX35 p.Arg101Ser Uncertain significance ★ ⚠ same type
DHX35 p.Arg109Gln Uncertain significance ★ ⚠ same type
DHX35 p.Arg109Gly Uncertain significance ★ ⚠ same type
DHX35 p.Arg110Gly 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/dhx35-p-val522ala (accessed [today's date]).

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