Is C2CD5 p.Thr503Ala (c.1507A>G) pathogenic?

C2CD5 p.Thr503Ala (c.1507A>G) is classified Uncertain significance in C2CD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0539); Ultra-rare (popmax 0.0585%, eas).

How common is C2CD5 p.Thr503Ala (c.1507A>G) in the general population?

C2CD5 p.Thr503Ala (c.1507A>G) is ultra-rare (popmax 0.0585%, eas) (gnomAD).

What do computational predictors say about C2CD5 p.Thr503Ala (c.1507A>G)?

AlphaMissense predicts likely benign (score 0.0539) — an in-silico prediction, not a clinical call.

C2CD5 p.Thr503Ala

c.1507A>G · rs62000366 · VCV3135915

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0539 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0585%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0539	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -6.80	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 -2.3	GERP -4.2
Regional constraint	o/e 0.93	unconstrained · MANE · 36 kb · p 0.099 · regional, not allelic
Overall
CADD	1.586	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 0.0585% East Asian · 26/44,452 alleles

Filtering AF 0.0409% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.0201% 322/1,601,878 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0585%	1,710
European (non-Finnish)	0.022%	4,555
Remaining individualsnot grpmax-eligible	0.021%	4,768
South Asian	0.0204%	4,905
Ashkenazi Jewishnot grpmax-eligible	0.0103%	9,732
Finnishnot grpmax-eligible	0.00314%	31,890
African / African-American	0.00269%	37,127

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.Thr503Ala
Coding: c.1507A>G
MANE Select: NM_001286176
dbSNP: rs62000366
Type: single nucleotide variant
Location: chr12:22484740 (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-thr503ala (accessed [today's date]).

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