Is C2CD4C p.Arg321Cys (c.961C>T) pathogenic?

C2CD4C p.Arg321Cys (c.961C>T) is classified Uncertain significance in C2CD4C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-26). AlphaMissense: likely benign (0.2832); Ultra-rare (popmax 0.0174%, mid).

How common is C2CD4C p.Arg321Cys (c.961C>T) in the general population?

C2CD4C p.Arg321Cys (c.961C>T) is ultra-rare (popmax 0.0174%, mid) (gnomAD).

What do computational predictors say about C2CD4C p.Arg321Cys (c.961C>T)?

AlphaMissense predicts likely benign (score 0.2832) — an in-silico prediction, not a clinical call.

C2CD4C p.Arg321Cys

c.961C>T · VCV3483553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2832 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2832	likely benign
REVEL	0.666	pathogenic-leaning
SaProt	LLR -10.21	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 0.67, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,262 bp · p 0.088 · regional, not allelic
Overall
CADD	27.2	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 0.0174% Middle Eastern · 1/5,744 alleles

Filtering AF 0.0015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00127%

Overall 0.00209% 32/1,534,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0174%	5,744
Finnishnot grpmax-eligible	0.00423%	23,629
African / African-American	0.00275%	36,395
East Asian	0.00246%	40,722
European (non-Finnish)	0.00218%	45,769
Remaining individualsnot grpmax-eligible	0.00167%	59,702

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: C2CD4C
Protein: p.Arg321Cys
Coding: c.961C>T
MANE Select: NM_001136263
Type: single nucleotide variant
Location: chr19:407401 (GRCh38)
Gene constraint: LOEUF 1.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.88
Residue 321: the c2 domain

Full C2CD4C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4C p.Ala107Thr Uncertain significance ★ ⚠ same type
C2CD4C p.Ala151Ser Uncertain significance ★ ⚠ same type
C2CD4C p.Ala154Ser Uncertain significance ★ ⚠ same type
C2CD4C p.Ala181Pro Uncertain significance ★ ⚠ same type
C2CD4C p.Ala187Val Uncertain significance ★ ⚠ same type
C2CD4C p.Ala203Val Uncertain significance ★ ⚠ same type
C2CD4C p.Ala248Thr Uncertain significance ★ ⚠ same type
C2CD4C p.Ala265Val 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/c2cd4c-p-arg321cys (accessed [today's date]).

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