Is DHX58 p.Ser169Phe (c.506C>T) pathogenic?

DHX58 p.Ser169Phe (c.506C>T) is classified Uncertain significance in DHX58 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.7953); Very rare (popmax 0.0011%, sas).

How common is DHX58 p.Ser169Phe (c.506C>T) in the general population?

DHX58 p.Ser169Phe (c.506C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DHX58 p.Ser169Phe (c.506C>T)?

AlphaMissense predicts likely pathogenic (score 0.7953) — an in-silico prediction, not a clinical call.

DHX58 p.Ser169Phe

c.506C>T · VCV4240405

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7953	likely pathogenic
REVEL	0.574	indeterminate
SaProt	LLR -13.77	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 7e-05 · regional, not allelic
Overall
CADD	27.3	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 0.0011% South Asian · 1/91,000 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,264 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,000
European (non-Finnish)	0.000254%	393,264

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: DHX58
Protein: p.Ser169Phe
Coding: c.506C>T
MANE Select: NM_024119
Type: single nucleotide variant
Location: chr17:42110778 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.15 · 5 PDB
Residue 169: the helicase atp-binding domain

Full DHX58 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DHX58 p.Gln425Arg Benign ★★ same type
DHX58 p.Ala110Thr Uncertain significance ★ ⚠ same type
DHX58 p.Ala302Pro Uncertain significance ★ ⚠ same type
DHX58 p.Ala304Val Uncertain significance ★ ⚠ same type
DHX58 p.Ala342Val Uncertain significance ★ ⚠ same type
DHX58 p.Ala35Val Uncertain significance ★ ⚠ same type
DHX58 p.Ala480Gly Uncertain significance ★ ⚠ same type
DHX58 p.Ala480Thr 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/dhx58-p-ser169phe (accessed [today's date]).

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