Is FDFT1 p.Pro249Leu (c.746C>T) pathogenic?

FDFT1 p.Pro249Leu (c.746C>T) is classified Uncertain significance in FDFT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely benign (0.1055); Ultra-rare (popmax 0.0165%, mid).

How common is FDFT1 p.Pro249Leu (c.746C>T) in the general population?

FDFT1 p.Pro249Leu (c.746C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about FDFT1 p.Pro249Leu (c.746C>T)?

AlphaMissense predicts likely benign (score 0.1055) — an in-silico prediction, not a clinical call.

FDFT1 p.Pro249Leu

c.746C>T · rs202060379 · VCV2403312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1055 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1055	likely benign
REVEL	0.691	pathogenic-leaning
SaProt	LLR -10.43	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.77	unconstrained · MANE · 36 kb · p 1.6e-69 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00341% 55/1,613,972 alleles · ultra-rare exomes 40/1,461,720 · genomes 15/152,252 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.01%	10,001
African / African-American	0.00933%	10,715
South Asian	0.00659%	15,179
East Asian	0.00446%	22,444
Remaining individualsnot grpmax-eligible	0.0032%	31,249
European (non-Finnish)	0.00263%	38,062

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: FDFT1
Protein: p.Pro249Leu
Coding: c.746C>T
MANE Select: NM_004462
dbSNP: rs202060379
Type: single nucleotide variant
Location: chr8:11830287 (GRCh38)
Gene constraint: LOEUF 1.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.14 · 32 PDB
Residue 249: an α-helix

Full FDFT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FDFT1 p.Pro249= Benign/Likely benign ★★ same residue
FDFT1 p.Pro249Arg Uncertain significance ★ ⚠ same residue
FDFT1 c.100-85G>C Uncertain significance ★★ same type
FDFT1 p.Ala333Ser Uncertain significance ★★ ⚠ same type
FDFT1 p.Asn265Ser Uncertain significance ★★ ⚠ same type
FDFT1 p.Gly151Asp Uncertain significance ★★ ⚠ same type
FDFT1 p.Ile252Thr Uncertain significance ★★ ⚠ same type
FDFT1 p.Phe210Leu 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/fdft1-p-pro249leu (accessed [today's date]).

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