Is MCCC2 p.Arg10Trp (c.28C>T) pathogenic?

MCCC2 p.Arg10Trp (c.28C>T) is classified Uncertain significance in MCCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-27). AlphaMissense: likely benign (0.2811); Very rare (popmax 8.73e-05%, nfe).

How common is MCCC2 p.Arg10Trp (c.28C>T) in the general population?

MCCC2 p.Arg10Trp (c.28C>T) is very rare (popmax 8.73e-05%, nfe) (gnomAD).

What do computational predictors say about MCCC2 p.Arg10Trp (c.28C>T)?

AlphaMissense predicts likely benign (score 0.2811) — an in-silico prediction, not a clinical call.

MCCC2 p.Arg10Trp

c.28C>T · VCV3768172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.73e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2811	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -10.54	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.66	GERP 1.7, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	17.49	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 8.73e-05% European (non-Finnish) · 1/1,146,092 alleles

Overall 7.23e-05% 1/1,382,810 alleles · very rare

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: MCCC2
Protein: p.Arg10Trp
Coding: c.28C>T
MANE Select: NM_022132
Type: single nucleotide variant
Location: chr5:71587453 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB

Full MCCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MCCC2 c.1000-2A>G Likely pathogenic ★★ same type
MCCC2 c.1072+1G>A Likely pathogenic ★★ same type
MCCC2 c.1149+1G>A Pathogenic/Likely pathogenic ★★ same type
MCCC2 c.1149+1G>T Pathogenic/Likely pathogenic ★★ same type
MCCC2 c.1216+1G>A Likely pathogenic ★★ same type
MCCC2 c.1216+2T>A Pathogenic/Likely pathogenic ★★ same type
MCCC2 c.1216+2T>C Likely pathogenic ★★ same type
MCCC2 c.129+1G>T Likely pathogenic ★★ 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/mccc2-p-arg10trp (accessed [today's date]).

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