Is C2CD6 p.Arg181Gln (c.542G>A) pathogenic?

C2CD6 p.Arg181Gln (c.542G>A) is classified Uncertain significance in C2CD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-12). AlphaMissense: likely benign (0.1459); Ultra-rare (popmax 0.0166%, mid).

How common is C2CD6 p.Arg181Gln (c.542G>A) in the general population?

C2CD6 p.Arg181Gln (c.542G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about C2CD6 p.Arg181Gln (c.542G>A)?

AlphaMissense predicts likely benign (score 0.1459) — an in-silico prediction, not a clinical call.

C2CD6 p.Arg181Gln

c.542G>A · VCV3262489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1459 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1459	likely benign
REVEL	0.568	indeterminate
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.43	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 3.2	GERP 1.1, phastCons 0.97
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.41 · regional, not allelic
Overall
CADD	22.8	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 0.0166% Middle Eastern · 1/6,040 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0079%

Overall 0.00882% 141/1,598,614 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,040
Remaining individualsnot grpmax-eligible	0.0113%	8,848
European (non-Finnish)	0.00995%	10,049
African / African-American	0.00811%	12,329
East Asian	0.00679%	14,734
South Asian	0.0046%	21,743
Finnishnot grpmax-eligible	0.00313%	31,922
Admixed American	0.00179%	55,750

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.Arg181Gln
Coding: c.542G>A
MANE Select: NM_001168221
Type: single nucleotide variant
Location: chr2:201582192 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 39.82
Residue 181: the c2 domain

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

Similar variants

C2CD6 p.Arg181Trp 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-arg181gln (accessed [today's date]).

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