Is MFF p.Val135Ile (c.403G>A) pathogenic?

MFF p.Val135Ile (c.403G>A) is classified Conflicting classifications of pathogenicity in MFF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0858); Rare (popmax 0.189%, afr); Associated with encephalopathy due to defective mitochondrial and peroxisomal fission 2.

What condition is associated with MFF p.Val135Ile (c.403G>A)?

MFF p.Val135Ile (c.403G>A) is associated with encephalopathy due to defective mitochondrial and peroxisomal fission 2 (ClinVar).

How common is MFF p.Val135Ile (c.403G>A) in the general population?

MFF p.Val135Ile (c.403G>A) is rare (popmax 0.189%, afr) (gnomAD).

What do computational predictors say about MFF p.Val135Ile (c.403G>A)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

MFF p.Val135Ile

c.403G>A · rs145143758 · VCV2176257

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.189%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

encephalopathy due to defective mitochondrial and peroxisomal fission 2

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 26 kb · p 0.33 · regional, not allelic
Overall
CADD	23.0	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 V161I vs ClinVar V135I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.189% African / African-American · 142/75,042 alleles

Filtering AF 0.164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.154%

Overall 0.0104% 168/1,614,018 alleles · rare exomes 89/1,461,718 · genomes 79/152,300 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.189%	528
Remaining individualsnot grpmax-eligible	0.024%	4,167
Admixed American	0.015%	6,669
European (non-Finnish)	0.00017%	589,971

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.Val135Ile
Coding: c.403G>A
MANE Select: NM_001277062
dbSNP: rs145143758
Type: single nucleotide variant
Location: chr2:227340343 (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

encephalopathy due to defective mitochondrial and peroxisomal fission 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Encephalopathy due to mitochondrial and peroxisomal fission defect (Orphanet):

Onset: Childhood, Infancy, Neonatal

Similar variants

MFF p.Asp75Asn Uncertain significance ★★ ⚠ same condition
MFF p.Ile250Ser Uncertain significance ★★ ⚠ same condition
MFF p.Ala210= Benign/Likely benign ★★ same condition
MFF p.Pro31Leu Benign/Likely benign ★★ same condition
MFF c.-40-841T>G Likely pathogenic ★ same condition
MFF c.-40-842G>T Likely pathogenic ★ same condition
MFF p.Ile226Met Uncertain significance ★ ⚠ same condition
MFF p.Pro113Thr 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-val135ile (accessed [today's date]).

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