Is MTFMT p.Leu296Pro (c.887T>C) pathogenic?

MTFMT p.Leu296Pro (c.887T>C) is classified Uncertain significance in MTFMT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0918); Ultra-rare (popmax 0.0626%, sas); Associated with Inborn genetic diseases.

What condition is associated with MTFMT p.Leu296Pro (c.887T>C)?

MTFMT p.Leu296Pro (c.887T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MTFMT p.Leu296Pro (c.887T>C) in the general population?

MTFMT p.Leu296Pro (c.887T>C) is ultra-rare (popmax 0.0626%, sas) (gnomAD).

What do computational predictors say about MTFMT p.Leu296Pro (c.887T>C)?

AlphaMissense predicts likely benign (score 0.0918) — an in-silico prediction, not a clinical call.

MTFMT p.Leu296Pro

c.887T>C · rs762770982 · VCV2614144

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0626%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0918	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -14.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.18 · regional, not allelic
Overall
CADD	21.9	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 0.0626% South Asian · 57/90,984 alleles

Filtering AF 0.0496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0449%

Overall 0.00372% 60/1,612,008 alleles · ultra-rare exomes 56/1,459,664 · genomes 4/152,344 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0626%	1,596
Middle Eastern	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.0016%	62,392

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.Leu296Pro
Coding: c.887T>C
MANE Select: NM_139242
dbSNP: rs762770982
Type: single nucleotide variant
Location: chr15:65006118 (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.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
MTFMT p.Gly33Asp 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-leu296pro (accessed [today's date]).

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