Is DHX34 p.Arg488Trp (c.1462C>T) pathogenic?

DHX34 p.Arg488Trp (c.1462C>T) is classified Uncertain significance in DHX34 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-08). AlphaMissense: likely pathogenic (0.9823); Ultra-rare (popmax 0.0934%, afr).

How common is DHX34 p.Arg488Trp (c.1462C>T) in the general population?

DHX34 p.Arg488Trp (c.1462C>T) is ultra-rare (popmax 0.0934%, afr) (gnomAD).

What do computational predictors say about DHX34 p.Arg488Trp (c.1462C>T)?

AlphaMissense predicts likely pathogenic (score 0.9823) — an in-silico prediction, not a clinical call.

DHX34 p.Arg488Trp

c.1462C>T · rs141007606 · VCV2402606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0934%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9823	likely pathogenic · top 4% in DHX34
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -15.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.95, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 29 kb · p 0.62 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0934% African / African-American · 70/74,970 alleles

Filtering AF 0.0757% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0693%

Overall 0.00558% 90/1,613,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0934%	1,071
Remaining individualsnot grpmax-eligible	0.0048%	20,821
East Asian	0.00223%	44,798
Admixed American	0.00167%	59,894
European (non-Finnish)	0.00119%	84,264
South Asian	0.0011%	90,964

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: DHX34
Protein: p.Arg488Trp
Coding: c.1462C>T
MANE Select: NM_014681
dbSNP: rs141007606
Type: single nucleotide variant
Location: chr19:47362562 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.85
Residue 488: a UniProt-annotated variant site (found in a patient with a neurodevelopmental disorder; uncertain significance); the helicase c-terminal domain

Full DHX34 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DHX34 p.Asn682Thr Uncertain significance ★★ ⚠ same type
DHX34 p.Ser624Arg Uncertain significance ★★ ⚠ same type
DHX34 p.Thr973Met Uncertain significance ★★ ⚠ same type
DHX34 c.3299-3T>C Benign ★★ same type
DHX34 c.3299-6C>T Likely benign ★★ same type
DHX34 p.Ala127Val Likely benign ★★ ⚠ same type
DHX34 p.Ala416Thr Benign/Likely benign ★★ same type
DHX34 p.Ala817Thr Benign ★★ 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/dhx34-p-arg488trp (accessed [today's date]).

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