Is GHDC p.Arg85Lys (c.254G>A) pathogenic?

GHDC p.Arg85Lys (c.254G>A) is classified Uncertain significance in GHDC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely benign (0.111); Very rare (popmax 0.00357%, nfe).

How common is GHDC p.Arg85Lys (c.254G>A) in the general population?

GHDC p.Arg85Lys (c.254G>A) is very rare (popmax 0.00357%, nfe) (gnomAD).

What do computational predictors say about GHDC p.Arg85Lys (c.254G>A)?

AlphaMissense predicts likely benign (score 0.111) — an in-silico prediction, not a clinical call.

GHDC p.Arg85Lys

c.254G>A · rs768472556 · VCV2466039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00357%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.111	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -7.68	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 -3	GERP -2.7
Regional constraint	o/e 0.75	unconstrained · MANE · 1,094 bp · p 7.1e-05 · regional, not allelic
Overall
CADD	0.067	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 0.00357% European (non-Finnish) · 42/1,174,864 alleles

Filtering AF 0.00268% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00237%

Overall 0.00275% 44/1,602,528 alleles · very rare exomes 43/1,450,304 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00357%	27,973
Remaining individualsnot grpmax-eligible	0.00161%	62,018
Finnishnot grpmax-eligible	0.00158%	63,152

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: GHDC
Protein: p.Arg85Lys
Coding: c.254G>A
MANE Select: NM_032484
dbSNP: rs768472556
Type: single nucleotide variant
Location: chr17:42193328 (GRCh38)
Gene constraint: LOEUF 1.127 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.77

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

Similar variants

GHDC p.Ala189Thr Uncertain significance ★ ⚠ same type
GHDC p.Ala223Val Uncertain significance ★ ⚠ same type
GHDC p.Ala225Gly Uncertain significance ★ ⚠ same type
GHDC p.Ala267Val Uncertain significance ★ ⚠ same type
GHDC p.Ala286Thr Uncertain significance ★ ⚠ same type
GHDC p.Ala291Thr Uncertain significance ★ ⚠ same type
GHDC p.Ala414Glu Uncertain significance ★ ⚠ same type
GHDC p.Ala436Thr 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/ghdc-p-arg85lys (accessed [today's date]).

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