Is C2CD2 p.Lys510Glu (c.1528A>G) pathogenic?

C2CD2 p.Lys510Glu (c.1528A>G) is classified Uncertain significance in C2CD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.8604); Ultra-rare (popmax 0.0659%, sas).

How common is C2CD2 p.Lys510Glu (c.1528A>G) in the general population?

C2CD2 p.Lys510Glu (c.1528A>G) is ultra-rare (popmax 0.0659%, sas) (gnomAD).

What do computational predictors say about C2CD2 p.Lys510Glu (c.1528A>G)?

AlphaMissense predicts likely pathogenic (score 0.8604) — an in-silico prediction, not a clinical call.

C2CD2 p.Lys510Glu

c.1528A>G · VCV3993932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0659%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8604	likely pathogenic · top 6% in C2CD2
REVEL	0.538	indeterminate
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 65 kb · p 0.00014 · regional, not allelic
Overall
CADD	25.0	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 0.0659% South Asian · 60/91,084 alleles

Filtering AF 0.0525% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0476%

Overall 0.0136% 219/1,614,212 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0659%	1,518
Middle Eastern	0.033%	3,031
African / African-American	0.0267%	3,752
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Admixed American	0.0133%	7,504
European (non-Finnish)	0.00992%	10,086
Finnishnot grpmax-eligible	0.00156%	64,048

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: C2CD2
Protein: p.Lys510Glu
Coding: c.1528A>G
MANE Select: NM_015500
Type: single nucleotide variant
Location: chr21:41901654 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.52

Full C2CD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD2 p.Pro104= Benign ★★ same type
C2CD2 p.Ala123Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala136Gly Uncertain significance ★ ⚠ same type
C2CD2 p.Ala146Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala189Thr Uncertain significance ★ ⚠ same type
C2CD2 p.Ala207Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala345Val Uncertain significance ★ ⚠ same type
C2CD2 p.Ala466Thr 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/c2cd2-p-lys510glu (accessed [today's date]).

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