Is MCCC1 p.Arg409Pro (c.1226G>C) pathogenic?

MCCC1 p.Arg409Pro (c.1226G>C) is classified Likely benign in MCCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely benign (0.1036); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with MCCC1 p.Arg409Pro (c.1226G>C)?

MCCC1 p.Arg409Pro (c.1226G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MCCC1 p.Arg409Pro (c.1226G>C) in the general population?

MCCC1 p.Arg409Pro (c.1226G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MCCC1 p.Arg409Pro (c.1226G>C)?

AlphaMissense predicts likely benign (score 0.1036) — an in-silico prediction, not a clinical call.

MCCC1 p.Arg409Pro

c.1226G>C · VCV3544079

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1036	likely benign
REVEL	0.443	indeterminate
SaProt	LLR -3.50	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 -8.7	GERP -4.5
Regional constraint	o/e 0.89	unconstrained · MANE · 84 kb · p 0.0012 · regional, not allelic
Overall
CADD	0.001	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 0.0011% South Asian · 1/91,078 alleles

Overall 6.2e-05% 1/1,614,078 alleles · very rare exomes 1/1,461,814 · genomes 0/152,264 · joint denominator

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: MCCC1
Protein: p.Arg409Pro
Coding: c.1226G>C
MANE Select: NM_020166
Type: single nucleotide variant
Location: chr3:183041608 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.53 · 14 PDB
Residue 409: the biotin carboxylation domain; an α-helix

Full MCCC1 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

MCCC1 p.Arg409Leu Uncertain significance ★★ ⚠ same residue
MCCC1 p.Arg409Gln Likely benign ★ same residue
MCCC1 p.Arg409Ter Pathogenic ★★ same residue
MCCC1 p.Arg409Gly Uncertain significance ★ ⚠ same residue
MCCC1 p.Ala101Thr Uncertain significance ★★ ⚠ same condition
MCCC1 p.Ala291= Uncertain significance ★★ same condition
MCCC1 p.Ala530Gly Uncertain significance ★★ ⚠ same condition
MCCC1 p.Arg281Gln 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/mccc1-p-arg409pro (accessed [today's date]).

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