Is C2CD3 p.Thr526Ile (c.1577C>T) pathogenic?

C2CD3 p.Thr526Ile (c.1577C>T) is classified Uncertain significance in C2CD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-31). AlphaMissense: likely benign (0.1412); Ultra-rare (popmax 0.0101%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Thr526Ile (c.1577C>T)?

C2CD3 p.Thr526Ile (c.1577C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C2CD3 p.Thr526Ile (c.1577C>T) in the general population?

C2CD3 p.Thr526Ile (c.1577C>T) is ultra-rare (popmax 0.0101%, nfe) (gnomAD).

What do computational predictors say about C2CD3 p.Thr526Ile (c.1577C>T)?

AlphaMissense predicts likely benign (score 0.1412) — an in-silico prediction, not a clinical call.

C2CD3 p.Thr526Ile

c.1577C>T · rs375030806 · VCV2057966

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1412 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1412	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -7.93	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 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	22.1	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 0.0101% European (non-Finnish) · 119/1,179,900 alleles

Filtering AF 0.00859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00804%

Overall 0.00762% 123/1,613,812 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0101%	9,915
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00134%	74,890

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.Thr526Ile
Coding: c.1577C>T
MANE Select: NM_001286577
dbSNP: rs375030806
Type: single nucleotide variant
Location: chr11:74114537 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 526: the c2 1 domain

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 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
C2CD3 p.Arg1183His 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-thr526ile (accessed [today's date]).

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