Is C2CD3 p.Ala1820Ser (c.5458G>T) pathogenic?

C2CD3 p.Ala1820Ser (c.5458G>T) is classified Uncertain significance in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0178%, eas); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Ala1820Ser (c.5458G>T)?

C2CD3 p.Ala1820Ser (c.5458G>T) is associated with Inborn genetic diseases (ClinVar).

How common is C2CD3 p.Ala1820Ser (c.5458G>T) in the general population?

C2CD3 p.Ala1820Ser (c.5458G>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about C2CD3 p.Ala1820Ser (c.5458G>T)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

C2CD3 p.Ala1820Ser

c.5458G>T · VCV3993959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.008	strongly benign-leaning
SaProt	LLR -4.88	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 1.5	GERP -2.6, phastCons 0.057
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	0.732	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 0.0178% East Asian · 8/44,866 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00062% 10/1,613,510 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,608
Remaining individualsnot grpmax-eligible	0.0032%	31,235

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.Ala1820Ser
Coding: c.5458G>T
MANE Select: NM_001286577
Type: single nucleotide variant
Location: chr11:74048242 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2CD3 p.Ala1820= Likely benign ★ same residue
C2CD3 c.2085+5G>A Uncertain significance ★★ same condition
C2CD3 c.4951+6C>T Uncertain significance ★★ same condition
C2CD3 p.Ala1382Pro Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala1777Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala95Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1122Ile Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1145His Uncertain significance ★★ ⚠ same condition

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-ala1820ser (accessed [today's date]).

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