Is MTFMT p.Leu77Phe (c.231A>T) pathogenic?

MTFMT p.Leu77Phe (c.231A>T) is classified Uncertain significance in MTFMT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-02). AlphaMissense: likely benign (0.1672); Very rare (popmax 0.00271%, nfe).

How common is MTFMT p.Leu77Phe (c.231A>T) in the general population?

MTFMT p.Leu77Phe (c.231A>T) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about MTFMT p.Leu77Phe (c.231A>T)?

AlphaMissense predicts likely benign (score 0.1672) — an in-silico prediction, not a clinical call.

MTFMT p.Leu77Phe

c.231A>T · rs780539907 · VCV1800501

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1672	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -2.9, phastCons 0.99
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.18 · regional, not allelic
Overall
CADD	17.41	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00271% European (non-Finnish) · 32/1,179,780 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00211% 34/1,613,672 alleles · very rare exomes 27/1,461,500 · genomes 7/152,172 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00271%	36,868
Remaining individualsnot grpmax-eligible	0.0016%	62,464
Finnishnot grpmax-eligible	0.00156%	64,014

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.Leu77Phe
Coding: c.231A>T
MANE Select: NM_139242
dbSNP: rs780539907
Type: single nucleotide variant
Location: chr15:65027019 (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

Similar variants

MTFMT c.722-2A>G Likely pathogenic ★★ same type
MTFMT p.Arg128Ter Pathogenic/Likely pathogenic ★★ same type
MTFMT p.Arg332Ter Pathogenic ★★ same type
MTFMT p.Ser125Leu Pathogenic/Likely pathogenic ★★ same type
MTFMT p.Ser209Leu Pathogenic ★★ ⚠ same type
MTFMT p.Trp9Ter Pathogenic ★★ same type
MTFMT p.Ala213Thr Uncertain significance ★★ ⚠ same type
MTFMT p.Ala280Val Uncertain significance ★★ ⚠ 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/mtfmt-p-leu77phe (accessed [today's date]).

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