Is C2CD5 p.Ser53Leu (c.158C>T) pathogenic?

C2CD5 p.Ser53Leu (c.158C>T) is classified Uncertain significance in C2CD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-22). AlphaMissense: likely pathogenic (0.9132); Very rare (popmax 0.00223%, eas).

How common is C2CD5 p.Ser53Leu (c.158C>T) in the general population?

C2CD5 p.Ser53Leu (c.158C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about C2CD5 p.Ser53Leu (c.158C>T)?

AlphaMissense predicts likely pathogenic (score 0.9132) — an in-silico prediction, not a clinical call.

C2CD5 p.Ser53Leu

c.158C>T · VCV3826325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9132	likely pathogenic
REVEL	0.663	pathogenic-leaning
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 18 kb · p 3.5e-12 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,770 alleles

Filtering AF 0.000362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000262%

Overall 0.000686% 11/1,603,264 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,770
African / African-American	0.00134%	74,602
European (non-Finnish)	0.000768%	130,131

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: C2CD5
Protein: p.Ser53Leu
Coding: c.158C>T
MANE Select: NM_001286176
Type: single nucleotide variant
Location: chr12:22535277 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.34
Residue 53: the c2 domain

Full C2CD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD5 p.Ala21Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala242Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala252Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala342Val Uncertain significance ★ ⚠ same type
C2CD5 p.Ala355Thr Uncertain significance ★ ⚠ same type
C2CD5 p.Ala405Val Uncertain significance ★ ⚠ same type
C2CD5 p.Ala433Val Uncertain significance ★ ⚠ same type
C2CD5 p.Ala527Thr 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/c2cd5-p-ser53leu (accessed [today's date]).

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