Is C2CD6 p.Arg135Cys (c.403C>T) pathogenic?

C2CD6 p.Arg135Cys (c.403C>T) is classified Uncertain significance in C2CD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely benign (0.1374); Ultra-rare (popmax 0.0482%, afr).

How common is C2CD6 p.Arg135Cys (c.403C>T) in the general population?

C2CD6 p.Arg135Cys (c.403C>T) is ultra-rare (popmax 0.0482%, afr) (gnomAD).

What do computational predictors say about C2CD6 p.Arg135Cys (c.403C>T)?

AlphaMissense predicts likely benign (score 0.1374) — an in-silico prediction, not a clinical call.

C2CD6 p.Arg135Cys

c.403C>T · VCV3483597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1374 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0482%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1374	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -8.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.37	acceptor loss · deltas
Pangolin	Δ0.32	loss · gain 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.3	GERP -0.74, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 83 kb · p 0.41 · regional, not allelic
Overall
CADD	22.7	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 0.0482% African / African-American · 36/74,730 alleles

Filtering AF 0.0358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0315%

Overall 0.00474% 76/1,603,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0482%	2,076
South Asian	0.0289%	3,466
Middle Eastern	0.0166%	6,020
East Asian	0.00224%	44,626
European (non-Finnish)	0.00102%	97,729

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.Arg135Cys
Coding: c.403C>T
MANE Select: NM_001168221
Type: single nucleotide variant
Location: chr2:201601852 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 39.82
Residue 135: the c2 domain

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

Similar variants

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
C2CD6 p.Arg1134His 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-arg135cys (accessed [today's date]).

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