Is MTFMT p.Phe345Leu (c.1035C>G) pathogenic?

MTFMT p.Phe345Leu (c.1035C>G) is classified Uncertain significance in MTFMT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: likely pathogenic (0.9474); Very rare (popmax 0.000254%, nfe).

How common is MTFMT p.Phe345Leu (c.1035C>G) in the general population?

MTFMT p.Phe345Leu (c.1035C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MTFMT p.Phe345Leu (c.1035C>G)?

AlphaMissense predicts likely pathogenic (score 0.9474) — an in-silico prediction, not a clinical call.

MTFMT p.Phe345Leu

c.1035C>G · rs1411892180 · VCV1467594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9474 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9474	likely pathogenic · top 4% in MTFMT
REVEL	0.394	indeterminate
SaProt	LLR -11.65	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.18 · regional, not allelic
Overall
CADD	28.0	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 0.000254% European (non-Finnish) · 3/1,179,806 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,654 alleles · very rare exomes 2/1,461,544 · genomes 1/152,110 · joint denominator

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.Phe345Leu
Coding: c.1035C>G
MANE Select: NM_139242
dbSNP: rs1411892180
Type: single nucleotide variant
Location: chr15:65003197 (GRCh38)
Gene constraint: LOEUF 1.304 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.08
Residue 345: a UniProt-annotated variant site (in mc1dn27)

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-phe345leu (accessed [today's date]).

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