Is C2CD3 p.Ser1663Asn (c.4988G>A) pathogenic?

C2CD3 p.Ser1663Asn (c.4988G>A) is classified Benign in C2CD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.3439); Common (popmax 9.73%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about C2CD3 p.Ser1663Asn (c.4988G>A)?

AlphaMissense predicts ambiguous (score 0.3439) — an in-silico prediction, not a clinical call.

C2CD3 p.Ser1663Asn

Q: How common is C2CD3 p.Ser1663Asn (c.4988G>A) in the general population?

C2CD3 p.Ser1663Asn (c.4988G>A) is common (popmax 9.73%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4988G>A · rs12419308 · VCV1246120

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3439 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.73%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3439	ambiguous
REVEL	0.088	moderately benign-leaning
SaProt	LLR -7.69	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	23.9	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 9.73% African / African-American · 7,296/74,988 alleles

Filtering AF 9.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.47%

Overall 2.98% 48,124/1,613,824 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.73%	10
Middle Eastern	8.25%	12
Ashkenazi Jewishnot grpmax-eligible	7.08%	14
Amishnot grpmax-eligible	5.37%	19
South Asian	3.99%	25
Remaining individualsnot grpmax-eligible	3.64%	27
Admixed American	3.24%	31
European (non-Finnish)	2.55%	39
Finnishnot grpmax-eligible	0.417%	240
East Asian	0.0111%	8,976

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.Ser1663Asn
Coding: c.4988G>A
MANE Select: NM_001286577
dbSNP: rs12419308
Type: single nucleotide variant
Location: chr11:74057508 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 1663: a UniProt-annotated variant site (in); the c2 6 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-ser1663asn (accessed [today's date]).

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