Is MFF p.Phe280Cys (c.839T>G) pathogenic?

MFF p.Phe280Cys (c.839T>G) is classified Uncertain significance in MFF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-25). AlphaMissense: likely pathogenic (0.6511); Ultra-rare (popmax 0.0217%, mid).

How common is MFF p.Phe280Cys (c.839T>G) in the general population?

MFF p.Phe280Cys (c.839T>G) is ultra-rare (popmax 0.0217%, mid) (gnomAD).

What do computational predictors say about MFF p.Phe280Cys (c.839T>G)?

AlphaMissense predicts likely pathogenic (score 0.6511) — an in-silico prediction, not a clinical call.

MFF p.Phe280Cys

c.839T>G · rs960566048 · VCV1922372

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6511 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6511	likely pathogenic
REVEL	0.611	indeterminate
SaProt	LLR -9.56	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	29.4	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 F331C vs ClinVar F280C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Middle Eastern · 1/4,608 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,612,416 alleles · ultra-rare exomes 5/1,460,054 · genomes 0/152,362 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0217%	4,608
European (non-Finnish)	0.000339%	294,997

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.Phe280Cys
Coding: c.839T>G
MANE Select: NM_001277062
dbSNP: rs960566048
Type: single nucleotide variant
Location: chr2:227357080 (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

Similar variants

MFF p.Arg128Trp Uncertain significance ★★ ⚠ same type
MFF p.Arg136Cys Uncertain significance ★★ ⚠ same type
MFF p.Arg136His Uncertain significance ★★ ⚠ same type
MFF p.Arg199His Uncertain significance ★★ ⚠ same type
MFF p.Arg6Gln Uncertain significance ★★ ⚠ same type
MFF p.Arg92His Uncertain significance ★★ ⚠ same type
MFF p.Asp75Asn Uncertain significance ★★ ⚠ same type
MFF p.Gln52His 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/mff-p-phe280cys (accessed [today's date]).

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