Is C2CD4A p.Arg45Pro (c.134G>C) pathogenic?

C2CD4A p.Arg45Pro (c.134G>C) is classified Uncertain significance in C2CD4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely pathogenic (0.8097); Ultra-rare (popmax 0.0166%, mid).

How common is C2CD4A p.Arg45Pro (c.134G>C) in the general population?

C2CD4A p.Arg45Pro (c.134G>C) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about C2CD4A p.Arg45Pro (c.134G>C)?

AlphaMissense predicts likely pathogenic (score 0.8097) — an in-silico prediction, not a clinical call.

C2CD4A p.Arg45Pro

c.134G>C · VCV4217270

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8097 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8097	likely pathogenic · top 4% in C2CD4A
REVEL	0.153	moderately benign-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,106 bp · p 0.13 · regional, not allelic
Overall
CADD	28.2	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 0.0166% Middle Eastern · 1/6,034 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00093% 15/1,612,794 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,034
Admixed American	0.00167%	60,018
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00102%	98,328

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: C2CD4A
Protein: p.Arg45Pro
Coding: c.134G>C
MANE Select: NM_207322
Type: single nucleotide variant
Location: chr15:62067747 (GRCh38)
Gene constraint: LOEUF 1.963 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.36

Full C2CD4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4A p.Ala102Thr Uncertain significance ★ ⚠ same type
C2CD4A p.Ala160Thr Uncertain significance ★ ⚠ same type
C2CD4A p.Ala192Glu Uncertain significance ★ ⚠ same type
C2CD4A p.Ala226Asp Uncertain significance ★ ⚠ same type
C2CD4A p.Ala318Thr Uncertain significance ★ ⚠ same type
C2CD4A p.Ala318Val Uncertain significance ★ ⚠ same type
C2CD4A p.Ala338Val Uncertain significance ★ ⚠ same type
C2CD4A p.Arg177Gly 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/c2cd4a-p-arg45pro (accessed [today's date]).

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