Is C2CD6 p.Arg176His (c.527G>A) pathogenic?

C2CD6 p.Arg176His (c.527G>A) is classified Uncertain significance in C2CD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-04). AlphaMissense: likely benign (0.1011); Very rare (popmax 0.00453%, eas).

How common is C2CD6 p.Arg176His (c.527G>A) in the general population?

C2CD6 p.Arg176His (c.527G>A) is very rare (popmax 0.00453%, eas) (gnomAD).

What do computational predictors say about C2CD6 p.Arg176His (c.527G>A)?

AlphaMissense predicts likely benign (score 0.1011) — an in-silico prediction, not a clinical call.

C2CD6 p.Arg176His

c.527G>A · rs756027630 · VCV3135972

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1011 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00453%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1011	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 1	GERP -0.73, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.41 · regional, not allelic
Overall
CADD	16.73	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 0.00453% East Asian · 2/44,188 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00216% 31/1,434,710 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00453%	22,094
European (non-Finnish)	0.0023%	43,445
Admixed American	0.00196%	50,994
Finnishnot grpmax-eligible	0.00157%	63,732

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: C2CD6
Protein: p.Arg176His
Coding: c.527G>A
MANE Select: NM_001168221
dbSNP: rs756027630
Type: single nucleotide variant
Location: chr2:201582207 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 39.82
Residue 176: the c2 domain

Full C2CD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD6 p.Arg176Cys Uncertain significance ★ ⚠ same residue
C2CD6 p.Ala1682Thr Uncertain significance ★ same type
C2CD6 p.Ala427Gly Uncertain significance ★ ⚠ same type
C2CD6 p.Ala54Pro Uncertain significance ★ ⚠ same type
C2CD6 p.Ala54Ser Uncertain significance ★ ⚠ same type
C2CD6 p.Ala646Ser Uncertain significance ★ same type
C2CD6 p.Ala827Asp Uncertain significance ★ same type
C2CD6 p.Arg1134Cys 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/c2cd6-p-arg176his (accessed [today's date]).

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