Is MCCC2 p.Phe387Cys (c.1160T>G) pathogenic?

MCCC2 p.Phe387Cys (c.1160T>G) is classified Uncertain significance in MCCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-17). AlphaMissense: likely pathogenic (0.9858); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with MCCC2 p.Phe387Cys (c.1160T>G)?

MCCC2 p.Phe387Cys (c.1160T>G) is associated with Inborn genetic diseases (ClinVar).

How common is MCCC2 p.Phe387Cys (c.1160T>G) in the general population?

MCCC2 p.Phe387Cys (c.1160T>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MCCC2 p.Phe387Cys (c.1160T>G)?

AlphaMissense predicts likely pathogenic (score 0.9858) — an in-silico prediction, not a clinical call.

MCCC2 p.Phe387Cys

c.1160T>G · VCV3544081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9858 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9858	likely pathogenic · top 2% in MCCC2
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -15.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,032 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,520 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.Phe387Cys
Coding: c.1160T>G
MANE Select: NM_022132
Type: single nucleotide variant
Location: chr5:71646221 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 387: an α-helix; the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region; a UniProt-annotated variant site (in mcc2d; uncertain significance)

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.Phe387Val Uncertain significance ★★ ⚠ 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
MCCC2 p.Asp110Asn 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-phe387cys (accessed [today's date]).

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