Is MCCC2 p.Leu286Phe (c.858A>C) pathogenic?

MCCC2 p.Leu286Phe (c.858A>C) is classified Uncertain significance in MCCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-04). AlphaMissense: likely benign (0.3092); Very rare (popmax 0.00934%, afr); Associated with Inborn genetic diseases.

What condition is associated with MCCC2 p.Leu286Phe (c.858A>C)?

MCCC2 p.Leu286Phe (c.858A>C) is associated with Inborn genetic diseases (ClinVar).

How common is MCCC2 p.Leu286Phe (c.858A>C) in the general population?

MCCC2 p.Leu286Phe (c.858A>C) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about MCCC2 p.Leu286Phe (c.858A>C)?

AlphaMissense predicts likely benign (score 0.3092) — an in-silico prediction, not a clinical call.

MCCC2 p.Leu286Phe

c.858A>C · VCV4624495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3092	likely benign
REVEL	0.765	pathogenic-leaning
SaProt	LLR -12.82	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.9	GERP 0.98, phastCons 0.97
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	21.6	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 0.00934% African / African-American · 7/74,946 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,614,058 alleles · very rare exomes 3/1,461,836 · genomes 4/152,222 · 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: MCCC2
Protein: p.Leu286Phe
Coding: c.858A>C
MANE Select: NM_022132
Type: single nucleotide variant
Location: chr5:71634997 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 286: an α-helix; the coa carboxyltransferase n-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 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
MCCC2 p.Asp110Asn Uncertain significance ★★ ⚠ same condition
MCCC2 p.Asp259Tyr 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-leu286phe (accessed [today's date]).

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