Is MCCC2 p.Ser39Phe (c.116C>T) pathogenic?

MCCC2 p.Ser39Phe (c.116C>T) is classified Uncertain significance in MCCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-13). AlphaMissense: likely benign (0.3376); Very rare (popmax 0.00137%, afr).

How common is MCCC2 p.Ser39Phe (c.116C>T) in the general population?

MCCC2 p.Ser39Phe (c.116C>T) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about MCCC2 p.Ser39Phe (c.116C>T)?

AlphaMissense predicts likely benign (score 0.3376) — an in-silico prediction, not a clinical call.

MCCC2 p.Ser39Phe

c.116C>T · rs398124371 · VCV96028

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3376 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3376	likely benign
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -15.49	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 4.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	27.7	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 0.00137% African / African-American · 1/73,216 alleles

Filtering AF 0.000515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000376%

Overall 0.00078% 12/1,537,718 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00137%	73,216
European (non-Finnish)	0.00096%	104,200

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.Ser39Phe
Coding: c.116C>T
MANE Select: NM_022132
dbSNP: rs398124371
Type: single nucleotide variant
Location: chr5:71587541 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 39: a UniProt-annotated variant site (in mcc2d; has some wild-type residual activity)

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

Similar variants

MCCC2 p.Ser39= Likely benign ★ same residue
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

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-ser39phe (accessed [today's date]).

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