Is DHX8 p.Pro18Leu (c.53C>T) pathogenic?

DHX8 p.Pro18Leu (c.53C>T) is classified Uncertain significance in DHX8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1229); Very rare (popmax 0.00667%, amr).

How common is DHX8 p.Pro18Leu (c.53C>T) in the general population?

DHX8 p.Pro18Leu (c.53C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about DHX8 p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.1229) — an in-silico prediction, not a clinical call.

DHX8 p.Pro18Leu

c.53C>T · VCV4240419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1229	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -4.61	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 5.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.28	unconstrained · MANE · 54 bp · p 0.17 · regional, not allelic
Overall
CADD	24.2	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 0.00667% Admixed American · 4/60,002 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,614,056 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
European (non-Finnish)	8.47e-05%	1,180,040

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: DHX8
Protein: p.Pro18Leu
Coding: c.53C>T
MANE Select: NM_004941
Type: single nucleotide variant
Location: chr17:43484090 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.83 · 25 PDB
Residue 18: an α-helix

Full DHX8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DHX8 c.3444-10C>T Benign ★★ same type
ETV4 c.1129-107C>T Benign ★★ same type
ETV4 c.256+103C>A Benign ★★ same type
ETV4 c.546-91G>A Benign ★★ same type
ETV4 p.Pro115Ser Likely benign ★★ same type
HRH1 p.Arg326Gln Benign ★★ same type
HRH1 p.Lys19Asn Benign ★★ same type
HRH1 p.Met14Ile 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/dhx8-p-pro18leu (accessed [today's date]).

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