Is C2CD3 p.Arg38Cys (c.112C>T) pathogenic?

C2CD3 p.Arg38Cys (c.112C>T) is classified Uncertain significance in C2CD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-27). AlphaMissense: ambiguous (0.4544); Ultra-rare (popmax 0.0111%, eas); Associated with congenital portosystemic shunt.

What condition is associated with C2CD3 p.Arg38Cys (c.112C>T)?

C2CD3 p.Arg38Cys (c.112C>T) is associated with congenital portosystemic shunt (ClinVar).

How common is C2CD3 p.Arg38Cys (c.112C>T) in the general population?

C2CD3 p.Arg38Cys (c.112C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about C2CD3 p.Arg38Cys (c.112C>T)?

AlphaMissense predicts ambiguous (score 0.4544) — an in-silico prediction, not a clinical call.

C2CD3 p.Arg38Cys

c.112C>T · rs764051582 · VCV1806580

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4544 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

congenital portosystemic shunt

Computational evidence

Protein change
AlphaMissense	0.4544	ambiguous
REVEL	0.233	benign-leaning
SaProt	LLR -5.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.84, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	29.7	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 0.0111% East Asian · 5/44,896 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.0057% 92/1,613,996 alleles · ultra-rare exomes 76/1,461,758 · genomes 16/152,238 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,979
African / African-American	0.00934%	10,707
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00576%	17,352
Admixed American	0.005%	20,002
South Asian	0.00439%	22,773
Finnishnot grpmax-eligible	0.00156%	64,038

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.Arg38Cys
Coding: c.112C>T
MANE Select: NM_001286577
dbSNP: rs764051582
Type: single nucleotide variant
Location: chr11:74168557 (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

congenital portosystemic shunt — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2CD3 p.Arg38His Uncertain significance ★ ⚠ same residue
C2CD3 p.Thr44Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
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

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-arg38cys (accessed [today's date]).

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