Is MTFMT p.Val159Ala (c.476T>C) pathogenic?

MTFMT p.Val159Ala (c.476T>C) is classified Benign in MTFMT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.4799); Rare (popmax 0.83%, sas).

How common is MTFMT p.Val159Ala (c.476T>C) in the general population?

MTFMT p.Val159Ala (c.476T>C) is rare (popmax 0.83%, sas) (gnomAD).

What do computational predictors say about MTFMT p.Val159Ala (c.476T>C)?

AlphaMissense predicts ambiguous (score 0.4799) — an in-silico prediction, not a clinical call.

MTFMT p.Val159Ala

c.476T>C · rs571610853 · VCV1291353

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4799 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.83%, sas)

Computational evidence

Protein change
AlphaMissense	0.4799	ambiguous
REVEL	0.503	indeterminate
SaProt	LLR -12.00	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.18 · regional, not allelic
Overall
CADD	26.3	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 0.83% South Asian · 756/91,046 alleles

Filtering AF 0.781% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.762%

Overall 0.0486% 784/1,613,714 alleles · rare exomes 739/1,461,352 · genomes 45/152,362 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.83%	120
Remaining individualsnot grpmax-eligible	0.0304%	3,288
Middle Eastern	0.0165%	6,060
Admixed American	0.00167%	60,014
African / African-American	0.00133%	75,054
European (non-Finnish)	0.000509%	196,612

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.Val159Ala
Coding: c.476T>C
MANE Select: NM_139242
dbSNP: rs571610853
Type: single nucleotide variant
Location: chr15:65023738 (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-val159ala (accessed [today's date]).

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