Is C2CD3 p.Thr2084Ser (c.6251C>G) pathogenic?

C2CD3 p.Thr2084Ser (c.6251C>G) is classified Conflicting classifications of pathogenicity in C2CD3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.2831); Rare (popmax 0.347%, sas).

How common is C2CD3 p.Thr2084Ser (c.6251C>G) in the general population?

C2CD3 p.Thr2084Ser (c.6251C>G) is rare (popmax 0.347%, sas) (gnomAD).

What do computational predictors say about C2CD3 p.Thr2084Ser (c.6251C>G)?

AlphaMissense predicts likely benign (score 0.2831) — an in-silico prediction, not a clinical call.

C2CD3 p.Thr2084Ser

c.6251C>G · rs562313391 · VCV1589925

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2831 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.347%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2831	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -5.49	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · 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 0.347% South Asian · 292/84,064 alleles

Filtering AF 0.315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.302%

Overall 0.0202% 310/1,536,278 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.347%	288
Middle Eastern	0.0334%	2,995
Remaining individualsnot grpmax-eligible	0.0183%	5,459
East Asian	0.00244%	40,916
Admixed American	0.00196%	51,008
African / African-American	0.00137%	73,182
European (non-Finnish)	0.000174%	573,473

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.Thr2084Ser
Coding: c.6251C>G
MANE Select: NM_001286577
dbSNP: rs562313391
Type: single nucleotide variant
Location: chr11:74033909 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 2084: the 'disordered' region

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-thr2084ser (accessed [today's date]).

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