Is HDHD5 p.Cys17Ser (c.50G>C) pathogenic?

HDHD5 p.Cys17Ser (c.50G>C) is classified Uncertain significance in HDHD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). AlphaMissense: likely benign (0.1026); Very rare (popmax 0.00318%, afr).

How common is HDHD5 p.Cys17Ser (c.50G>C) in the general population?

HDHD5 p.Cys17Ser (c.50G>C) is very rare (popmax 0.00318%, afr) (gnomAD).

What do computational predictors say about HDHD5 p.Cys17Ser (c.50G>C)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

HDHD5 p.Cys17Ser

c.50G>C · rs1028162017 · VCV3104716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00318%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -6.19	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 0.066	GERP -0.2, phastCons 0.001
Regional constraint	o/e 1.05	unconstrained · MANE · 21 kb · p 0.22 · regional, not allelic
Overall
CADD	7.686	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 0.00318% African / African-American · 2/62,902 alleles

Filtering AF 0.000527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000197%

Overall 0.000247% 3/1,213,614 alleles · very rare exomes 0/1,063,508 · genomes 3/150,106 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00318%	31,451
European (non-Finnish)	0.000102%	977,278

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: HDHD5
Protein: p.Cys17Ser
Coding: c.50G>C
MANE Select: NM_033070
dbSNP: rs1028162017
Type: single nucleotide variant
Location: chr22:17159202 (GRCh38)
Gene constraint: LOEUF 1.287 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.64

Full HDHD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDHD5 p.Arg369Ser Benign ★★ same type
HDHD5 p.Arg416Cys Likely benign ★★ same type
HDHD5 p.Ala223Thr Uncertain significance ★ ⚠ same type
HDHD5 p.Ala24Pro Uncertain significance ★ ⚠ same type
HDHD5 p.Ala25Val Uncertain significance ★ ⚠ same type
HDHD5 p.Ala2Thr Uncertain significance ★ ⚠ same type
HDHD5 p.Ala2Val Uncertain significance ★ ⚠ same type
HDHD5 p.Ala342Ser 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/hdhd5-p-cys17ser (accessed [today's date]).

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