Is DHX35 p.Ser46Pro (c.136T>C) pathogenic?

DHX35 p.Ser46Pro (c.136T>C) is classified Uncertain significance in DHX35 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: likely benign (0.1896); Very rare (popmax 0.00167%, amr).

How common is DHX35 p.Ser46Pro (c.136T>C) in the general population?

DHX35 p.Ser46Pro (c.136T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DHX35 p.Ser46Pro (c.136T>C)?

AlphaMissense predicts likely benign (score 0.1896) — an in-silico prediction, not a clinical call.

DHX35 p.Ser46Pro

c.136T>C · rs1240043162 · VCV2406577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1896 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1896	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -2.57	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 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 76 kb · p 0.22 · regional, not allelic
Overall
CADD	22.4	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 0.00167% Admixed American · 1/59,702 alleles

Overall 0.000124% 2/1,612,856 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,702
African / African-American	0.00134%	74,874

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.Ser46Pro
Coding: c.136T>C
MANE Select: NM_021931
dbSNP: rs1240043162
Type: single nucleotide variant
Location: chr20:38969176 (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-ser46pro (accessed [today's date]).

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