Is MFF p.Pro31Leu (c.92C>T) pathogenic?

MFF p.Pro31Leu (c.92C>T) is classified Benign/Likely benign in MFF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.1306); Rare (popmax 0.833%, afr); Associated with encephalopathy due to defective mitochondrial and peroxisomal fission 2.

What condition is associated with MFF p.Pro31Leu (c.92C>T)?

MFF p.Pro31Leu (c.92C>T) is associated with encephalopathy due to defective mitochondrial and peroxisomal fission 2 (ClinVar).

How common is MFF p.Pro31Leu (c.92C>T) in the general population?

MFF p.Pro31Leu (c.92C>T) is rare (popmax 0.833%, afr) (gnomAD).

What do computational predictors say about MFF p.Pro31Leu (c.92C>T)?

AlphaMissense predicts likely benign (score 0.1306) — an in-silico prediction, not a clinical call.

MFF p.Pro31Leu

c.92C>T · rs149692814 · VCV1577363

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1306 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.833%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

encephalopathy due to defective mitochondrial and peroxisomal fission 2

Computational evidence

Protein change
AlphaMissense	0.1306	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -3.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 26 kb · p 0.33 · regional, not allelic
Overall
CADD	28.6	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 P57L vs ClinVar P31L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.833% African / African-American · 625/75,028 alleles

Filtering AF 0.779% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.757%

Overall 0.0517% 834/1,614,152 alleles · rare exomes 437/1,461,864 · genomes 397/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.833%	120
Admixed American	0.13%	770
Finnishnot grpmax-eligible	0.075%	1,334
Remaining individualsnot grpmax-eligible	0.064%	1,563
Middle Eastern	0.0495%	2,019
European (non-Finnish)	0.00322%	31,053
East Asian	0.00223%	44,880
South Asian	0.0011%	91,078

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.Pro31Leu
Coding: c.92C>T
MANE Select: NM_001277062
dbSNP: rs149692814
Type: single nucleotide variant
Location: chr2:227330757 (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 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
MFF p.Trp286Arg 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-pro31leu (accessed [today's date]).

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