Is C2CD3 p.Ala1127Thr (c.3379G>A) pathogenic?

C2CD3 p.Ala1127Thr (c.3379G>A) is classified Uncertain significance in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-22). AlphaMissense: likely pathogenic (0.7693); Ultra-rare (popmax 0.0253%, sas).

How common is C2CD3 p.Ala1127Thr (c.3379G>A) in the general population?

C2CD3 p.Ala1127Thr (c.3379G>A) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about C2CD3 p.Ala1127Thr (c.3379G>A)?

AlphaMissense predicts likely pathogenic (score 0.7693) — an in-silico prediction, not a clinical call.

C2CD3 p.Ala1127Thr

c.3379G>A · rs200638603 · VCV1408524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7693	likely pathogenic
REVEL	0.314	indeterminate
SaProt	LLR -12.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0253% South Asian · 23/91,048 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00174% 28/1,613,748 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,959
Admixed American	0.00167%	59,984
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	74,990
European (non-Finnish)	0.00017%	589,908

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: C2CD3
Protein: p.Ala1127Thr
Coding: c.3379G>A
MANE Select: NM_001286577
dbSNP: rs200638603
Type: single nucleotide variant
Location: chr11:74092554 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1127: the c2 3 domain

Full C2CD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg666Ter Pathogenic ★★ same type
C2CD3 p.Arg768Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Tyr173Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 c.2085+5G>A Uncertain significance ★★ same type
C2CD3 c.4951+6C>T Uncertain significance ★★ same type
C2CD3 c.5495+4A>G 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/c2cd3-p-ala1127thr (accessed [today's date]).

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