Is C2CD4C p.Ala82Pro (c.244G>C) pathogenic?

C2CD4C p.Ala82Pro (c.244G>C) is classified Uncertain significance in C2CD4C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.0681); Ultra-rare (popmax 0.0578%, mid).

How common is C2CD4C p.Ala82Pro (c.244G>C) in the general population?

C2CD4C p.Ala82Pro (c.244G>C) is ultra-rare (popmax 0.0578%, mid) (gnomAD).

What do computational predictors say about C2CD4C p.Ala82Pro (c.244G>C)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

C2CD4C p.Ala82Pro

c.244G>C · VCV3994004

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0578%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.54	GERP -3.1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,262 bp · p 0.088 · regional, not allelic
Overall
CADD	4.351	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 0.0578% Middle Eastern · 3/5,192 alleles

Filtering AF 0.0157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00837%

Overall 0.00326% 48/1,470,624 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0578%	1,731
Remaining individualsnot grpmax-eligible	0.00531%	18,825
European (non-Finnish)	0.00368%	27,140
African / African-American	0.00144%	69,608

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.Ala82Pro
Coding: c.244G>C
MANE Select: NM_001136263
Type: single nucleotide variant
Location: chr19:408118 (GRCh38)
Gene constraint: LOEUF 1.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.88
Residue 82: the 'disordered' region

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

Similar variants

C2CD4C p.Ala82Val Uncertain significance ★ ⚠ same residue
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

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-ala82pro (accessed [today's date]).

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