Is MFF p.Ile250Ser (c.749T>G) pathogenic?

MFF p.Ile250Ser (c.749T>G) is classified Uncertain significance in MFF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-24). AlphaMissense: likely pathogenic (0.8659); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with MFF p.Ile250Ser (c.749T>G)?

MFF p.Ile250Ser (c.749T>G) is associated with Inborn genetic diseases, encephalopathy due to defective mitochondrial and peroxisomal fission 2 (ClinVar).

How common is MFF p.Ile250Ser (c.749T>G) in the general population?

MFF p.Ile250Ser (c.749T>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about MFF p.Ile250Ser (c.749T>G)?

AlphaMissense predicts likely pathogenic (score 0.8659) — an in-silico prediction, not a clinical call.

MFF p.Ile250Ser

c.749T>G · rs1278600625 · VCV1029745

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8659 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8659	likely pathogenic
REVEL	0.434	indeterminate
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 26 kb · p 0.33 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I301S vs ClinVar I250S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,714 alleles

Overall 6.21e-05% 1/1,609,226 alleles · very rare exomes 0/1,457,000 · genomes 1/152,226 · 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: MFF
Protein: p.Ile250Ser
Coding: c.749T>G
MANE Select: NM_001277062
dbSNP: rs1278600625
Type: single nucleotide variant
Location: chr2:227356990 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 64.74

Full MFF 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

Also linked: encephalopathy due to defective mitochondrial and peroxisomal fission 2

Similar variants

MFF p.Ile250Val Uncertain significance ★ ⚠ same residue
MFF p.Arg128Trp Uncertain significance ★★ ⚠ same condition
MFF p.Arg136His Uncertain significance ★★ ⚠ same condition
MFF p.Arg6Gln Uncertain significance ★★ ⚠ same condition
MFF p.Arg92His Uncertain significance ★★ ⚠ same condition
MFF p.Asp75Asn Uncertain significance ★★ ⚠ same condition
MFF p.Gln52His Uncertain significance ★★ ⚠ same condition
MFF p.His215Pro 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/mff-p-ile250ser (accessed [today's date]).

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