Is MTFMT p.Pro12Leu (c.35C>T) pathogenic?

MTFMT p.Pro12Leu (c.35C>T) is classified Conflicting classifications of pathogenicity in MTFMT (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-19). AlphaMissense: likely benign (0.0927); Rare (popmax 0.218%, afr); Associated with Inborn genetic diseases.

What condition is associated with MTFMT p.Pro12Leu (c.35C>T)?

MTFMT p.Pro12Leu (c.35C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MTFMT p.Pro12Leu (c.35C>T) in the general population?

MTFMT p.Pro12Leu (c.35C>T) is rare (popmax 0.218%, afr) (gnomAD).

What do computational predictors say about MTFMT p.Pro12Leu (c.35C>T)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

MTFMT p.Pro12Leu

c.35C>T · rs774208069 · VCV1526296

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.218%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -3.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.18 · regional, not allelic
Overall
CADD	2.499	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 0.218% African / African-American · 151/69,132 alleles

Filtering AF 0.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.179%

Overall 0.0121% 182/1,498,780 alleles · rare exomes 90/1,346,590 · genomes 92/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.218%	458
Remaining individualsnot grpmax-eligible	0.00864%	11,571
Admixed American	0.00856%	11,688
European (non-Finnish)	0.00196%	51,104

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: MTFMT
Protein: p.Pro12Leu
Coding: c.35C>T
MANE Select: NM_139242
dbSNP: rs774208069
Type: single nucleotide variant
Location: chr15:65029579 (GRCh38)
Gene constraint: LOEUF 1.304 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.08

Full MTFMT 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

MTFMT p.Pro12Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MTFMT p.Ala280Val Uncertain significance ★★ ⚠ same condition
MTFMT p.Ala383Gly Uncertain significance ★★ ⚠ same condition
MTFMT p.Arg154His Uncertain significance ★★ ⚠ same condition
MTFMT p.Arg21Thr Uncertain significance ★★ ⚠ same condition
MTFMT p.Arg31Pro Uncertain significance ★★ ⚠ same condition
MTFMT p.Arg371Lys Uncertain significance ★★ ⚠ same condition
MTFMT p.Glu259Gly 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/mtfmt-p-pro12leu (accessed [today's date]).

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