Is C2CD4D p.Pro334Ser (c.1000C>T) pathogenic?

C2CD4D p.Pro334Ser (c.1000C>T) is classified Uncertain significance in C2CD4D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: likely benign (0.2108); Very rare (popmax 0.0041%, afr).

How common is C2CD4D p.Pro334Ser (c.1000C>T) in the general population?

C2CD4D p.Pro334Ser (c.1000C>T) is very rare (popmax 0.0041%, afr) (gnomAD).

What do computational predictors say about C2CD4D p.Pro334Ser (c.1000C>T)?

AlphaMissense predicts likely benign (score 0.2108) — an in-silico prediction, not a clinical call.

C2CD4D p.Pro334Ser

c.1000C>T · VCV3262480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2108 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0041%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2108	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -10.53	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.2, phastCons 1
Overall
CADD	24.0	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 0.0041% African / African-American · 3/73,162 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000502%

Overall 0.000387% 6/1,550,188 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0041%	24,387
East Asian	0.00245%	40,824
European (non-Finnish)	0.000174%	573,109

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: C2CD4D
Protein: p.Pro334Ser
Coding: c.1000C>T
MANE Select: NM_001394591
Type: single nucleotide variant
Location: chr1:151837990 (GRCh38)
Gene constraint: LOEUF 1.931 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 66.41
Residue 334: the c2 domain

Full C2CD4D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4D p.Ala120Val Uncertain significance ★ ⚠ same type
C2CD4D p.Ala301Gly Uncertain significance ★ ⚠ same type
C2CD4D p.Ala31Ser Uncertain significance ★ ⚠ same type
C2CD4D p.Ala38Pro Uncertain significance ★ ⚠ same type
C2CD4D p.Ala63Glu Uncertain significance ★ ⚠ same type
C2CD4D p.Ala78Thr Uncertain significance ★ ⚠ same type
C2CD4D p.Arg102Trp Uncertain significance ★ ⚠ same type
C2CD4D p.Arg185His 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/c2cd4d-p-pro334ser (accessed [today's date]).

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