Is C2CD4B p.Arg111Cys (c.331C>T) pathogenic?

C2CD4B p.Arg111Cys (c.331C>T) is classified Uncertain significance in C2CD4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.5073); Ultra-rare (popmax 0.0158%, amr).

How common is C2CD4B p.Arg111Cys (c.331C>T) in the general population?

C2CD4B p.Arg111Cys (c.331C>T) is ultra-rare (popmax 0.0158%, amr) (gnomAD).

What do computational predictors say about C2CD4B p.Arg111Cys (c.331C>T)?

AlphaMissense predicts ambiguous (score 0.5073) — an in-silico prediction, not a clinical call.

C2CD4B p.Arg111Cys

c.331C>T · rs1345678794 · VCV2552095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5073 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, amr)

Computational evidence

Protein change
AlphaMissense	0.5073	ambiguous
REVEL	0.552	indeterminate
SaProt	LLR -6.19	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,091 bp · p 0.0058 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0158% Admixed American · 6/38,032 alleles

Filtering AF 0.00685% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00576%

Overall 0.00638% 91/1,426,474 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0158%	6,339
European (non-Finnish)	0.0076%	13,152
Remaining individualsnot grpmax-eligible	0.00367%	27,211

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: C2CD4B
Protein: p.Arg111Cys
Coding: c.331C>T
MANE Select: NM_001007595
dbSNP: rs1345678794
Type: single nucleotide variant
Location: chr15:62164654 (GRCh38)
Structure: AlphaFold pLDDT 60.81

Full C2CD4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4B p.Ala138Thr Uncertain significance ★ ⚠ same type
C2CD4B p.Ala190Gly Uncertain significance ★ ⚠ same type
C2CD4B p.Ala197Val Uncertain significance ★ ⚠ same type
C2CD4B p.Ala20Asp Uncertain significance ★ ⚠ same type
C2CD4B p.Ala231Pro Uncertain significance ★ ⚠ same type
C2CD4B p.Ala239Val Uncertain significance ★ ⚠ same type
C2CD4B p.Ala244Thr Uncertain significance ★ ⚠ same type
C2CD4B p.Ala244Val 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/c2cd4b-p-arg111cys (accessed [today's date]).

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