Is MCCC2 p.Arg492Gln (c.1475G>A) pathogenic?

MCCC2 p.Arg492Gln (c.1475G>A) is classified Uncertain significance in MCCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely benign (0.1323); Very rare (popmax 0.00878%, sas); Associated with Inborn genetic diseases.

What condition is associated with MCCC2 p.Arg492Gln (c.1475G>A)?

MCCC2 p.Arg492Gln (c.1475G>A) is associated with Inborn genetic diseases (ClinVar).

How common is MCCC2 p.Arg492Gln (c.1475G>A) in the general population?

MCCC2 p.Arg492Gln (c.1475G>A) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about MCCC2 p.Arg492Gln (c.1475G>A)?

AlphaMissense predicts likely benign (score 0.1323) — an in-silico prediction, not a clinical call.

MCCC2 p.Arg492Gln

c.1475G>A · VCV4104952

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1323 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1323	likely benign
REVEL	0.543	indeterminate
SaProt	LLR -12.37	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 4.5	GERP 0.78, phastCons 0.96
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · 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 0.00878% South Asian · 8/91,090 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.0031% 50/1,613,950 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,386
Admixed American	0.00333%	29,997
European (non-Finnish)	0.00322%	31,051
Remaining individualsnot grpmax-eligible	0.0032%	31,240

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.Arg492Gln
Coding: c.1475G>A
MANE Select: NM_022132
Type: single nucleotide variant
Location: chr5:71650170 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 492: an α-helix; the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region

Full MCCC2 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

MCCC2 p.Arg492Trp Uncertain significance ★ ⚠ same residue
MCCC2 p.Arg492= Likely benign ★ same residue
MCCC2 c.281+4C>T Uncertain significance ★★ same condition
MCCC2 p.Ala428Thr Uncertain significance ★★ ⚠ same condition
MCCC2 p.Ala551Thr Uncertain significance ★★ ⚠ same condition
MCCC2 p.Arg234His Uncertain significance ★★ ⚠ same condition
MCCC2 p.Asn205Lys Uncertain significance ★★ ⚠ same condition
MCCC2 p.Asn480Asp 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/mccc2-p-arg492gln (accessed [today's date]).

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