Is C2CD3 p.Ser1366Leu (c.4097C>T) pathogenic?

C2CD3 p.Ser1366Leu (c.4097C>T) is classified Conflicting classifications of pathogenicity in C2CD3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-26). AlphaMissense: likely benign (0.19); Ultra-rare (popmax 0.0263%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Ser1366Leu (c.4097C>T)?

C2CD3 p.Ser1366Leu (c.4097C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C2CD3 p.Ser1366Leu (c.4097C>T) in the general population?

C2CD3 p.Ser1366Leu (c.4097C>T) is ultra-rare (popmax 0.0263%, nfe) (gnomAD).

What do computational predictors say about C2CD3 p.Ser1366Leu (c.4097C>T)?

AlphaMissense predicts likely benign (score 0.19) — an in-silico prediction, not a clinical call.

C2CD3 p.Ser1366Leu

c.4097C>T · rs144630140 · VCV1315114

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.19 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.19	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	27.9	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 0.0263% European (non-Finnish) · 310/1,180,030 alleles

Filtering AF 0.0238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.0215% 347/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0266%	3,766
European (non-Finnish)grpmax	0.0263%	3,807
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Admixed American	0.00667%	14,997
African / African-American	0.00534%	18,734
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser1366Leu
Coding: c.4097C>T
MANE Select: NM_001286577
dbSNP: rs144630140
Type: single nucleotide variant
Location: chr11:74078621 (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.Ser1366= 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-ser1366leu (accessed [today's date]).

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