Is C2CD2L p.Cys385Trp (c.1155C>G) pathogenic?

C2CD2L p.Cys385Trp (c.1155C>G) is classified Uncertain significance in C2CD2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.3605); Very rare (popmax 0.00668%, eas).

How common is C2CD2L p.Cys385Trp (c.1155C>G) in the general population?

C2CD2L p.Cys385Trp (c.1155C>G) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about C2CD2L p.Cys385Trp (c.1155C>G)?

AlphaMissense predicts ambiguous (score 0.3605) — an in-silico prediction, not a clinical call.

C2CD2L p.Cys385Trp

c.1155C>G · VCV4217227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3605	ambiguous
REVEL	0.202	benign-leaning
SaProt	LLR -8.04	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.2	GERP -1.4, phastCons 0.97
Regional constraint	o/e 0.86	unconstrained · MANE · 8,511 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	21.7	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 0.00668% East Asian · 3/44,878 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000205% 3/1,460,920 alleles · very rare

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.Cys385Trp
Coding: c.1155C>G
MANE Select: NM_001290474
Type: single nucleotide variant
Location: chr11:119112552 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 64.75 · 1 PDB
Residue 385: the c2 domain

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

Similar variants

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
C2CD2L p.Ala524Thr 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-cys385trp (accessed [today's date]).

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