Is C2CD2L p.Arg347Trp (c.1039C>T) pathogenic?

C2CD2L p.Arg347Trp (c.1039C>T) is classified Uncertain significance in C2CD2L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely benign (0.1629); Ultra-rare (popmax 0.0367%, mid).

How common is C2CD2L p.Arg347Trp (c.1039C>T) in the general population?

C2CD2L p.Arg347Trp (c.1039C>T) is ultra-rare (popmax 0.0367%, mid) (gnomAD).

What do computational predictors say about C2CD2L p.Arg347Trp (c.1039C>T)?

AlphaMissense predicts likely benign (score 0.1629) — an in-silico prediction, not a clinical call.

C2CD2L p.Arg347Trp

c.1039C>T · VCV3262449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1629	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -10.71	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 3.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,511 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	26.2	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 0.0367% Middle Eastern · 2/5,448 alleles

Filtering AF 0.00642% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00124% 20/1,612,744 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0367%	2,724
Admixed American	0.01%	9,995
African / African-American	0.00134%	74,858
European (non-Finnish)	0.000932%	107,250

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: C2CD2L
Protein: p.Arg347Trp
Coding: c.1039C>T
MANE Select: NM_001290474
Type: single nucleotide variant
Location: chr11:119112347 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 64.75 · 1 PDB
Residue 347: the c2 domain

Full C2CD2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD2L p.Arg347Gln Uncertain significance ★ ⚠ same residue
C2CD2L c.451-8G>A Benign ★★ same type
C2CD2L p.Ala14Thr Uncertain significance ★ ⚠ same type
C2CD2L p.Ala173Thr Uncertain significance ★ ⚠ same type
C2CD2L p.Ala245Ser Uncertain significance ★ ⚠ same type
C2CD2L p.Ala245Thr Uncertain significance ★ ⚠ same type
C2CD2L p.Ala326Val Uncertain significance ★ ⚠ same type
C2CD2L p.Ala512Val 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/c2cd2l-p-arg347trp (accessed [today's date]).

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