Is MFF p.Ile230Thr (c.689T>C) pathogenic?

MFF p.Ile230Thr (c.689T>C) is classified Uncertain significance in MFF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-24). AlphaMissense: likely benign (0.0747); Ultra-rare (popmax 0.0867%, afr); Associated with Inborn genetic diseases.

What condition is associated with MFF p.Ile230Thr (c.689T>C)?

MFF p.Ile230Thr (c.689T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MFF p.Ile230Thr (c.689T>C) in the general population?

MFF p.Ile230Thr (c.689T>C) is ultra-rare (popmax 0.0867%, afr) (gnomAD).

What do computational predictors say about MFF p.Ile230Thr (c.689T>C)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

MFF p.Ile230Thr

c.689T>C · rs145321987 · VCV1371186

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0867%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -5.54	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 1.6	GERP 1.1, phastCons 0.021
Regional constraint	o/e 0.95	unconstrained · MANE · 26 kb · p 0.33 · regional, not allelic
Overall
CADD	19.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I281T vs ClinVar I230T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0867% African / African-American · 65/74,996 alleles

Filtering AF 0.0698% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0636%

Overall 0.00521% 84/1,611,396 alleles · ultra-rare exomes 55/1,459,070 · genomes 29/152,326 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0867%	1,154
Middle Eastern	0.0661%	1,512
Remaining individualsnot grpmax-eligible	0.0144%	6,935
Admixed American	0.00667%	14,997
South Asian	0.0011%	90,968
European (non-Finnish)	8.49e-05%	1,177,662

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.Ile230Thr
Coding: c.689T>C
MANE Select: NM_001277062
dbSNP: rs145321987
Type: single nucleotide variant
Location: chr2:227355706 (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

Similar variants

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.Gln52His Uncertain significance ★★ ⚠ same condition
MFF p.His215Pro Uncertain significance ★★ ⚠ same condition
MFF p.Ile250Ser Uncertain significance ★★ ⚠ same condition
MFF p.Ile50Leu 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-ile230thr (accessed [today's date]).

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