Is C2CD5 p.Ser250Cys (c.748A>T) pathogenic?

C2CD5 p.Ser250Cys (c.748A>T) is classified Uncertain significance in C2CD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely benign (0.0794); Ultra-rare (popmax 0.0267%, amr).

How common is C2CD5 p.Ser250Cys (c.748A>T) in the general population?

C2CD5 p.Ser250Cys (c.748A>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about C2CD5 p.Ser250Cys (c.748A>T)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

C2CD5 p.Ser250Cys

c.748A>T · VCV3483577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.44 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/59,978 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00118% 19/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,749
European (non-Finnish)	0.000254%	393,338

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.Ser250Cys
Coding: c.748A>T
MANE Select: NM_001286176
Type: single nucleotide variant
Location: chr12:22523478 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.34

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-ser250cys (accessed [today's date]).

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