Is FAT1 p.Pro3418Leu (c.10253C>T) pathogenic?

FAT1 p.Pro3418Leu (c.10253C>T) is classified Uncertain significance in FAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.1286); Ultra-rare (popmax 0.0117%, amr); Associated with Inborn genetic diseases.

What condition is associated with FAT1 p.Pro3418Leu (c.10253C>T)?

FAT1 p.Pro3418Leu (c.10253C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FAT1 p.Pro3418Leu (c.10253C>T) in the general population?

FAT1 p.Pro3418Leu (c.10253C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about FAT1 p.Pro3418Leu (c.10253C>T)?

AlphaMissense predicts likely benign (score 0.1286) — an in-silico prediction, not a clinical call.

FAT1 p.Pro3418Leu

c.10253C>T · rs199518914 · VCV2386587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1286 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1286	likely benign
REVEL	0.658	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 25 kb · p 0.00038 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,902 alleles

Filtering AF 0.00749% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.007%

Overall 0.00725% 117/1,613,098 alleles · ultra-rare exomes 113/1,461,636 · genomes 4/151,462 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,557
European (non-Finnish)	0.0089%	11,236
Remaining individualsnot grpmax-eligible	0.00801%	12,490

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: FAT1
Protein: p.Pro3418Leu
Coding: c.10253C>T
MANE Select: NM_005245
dbSNP: rs199518914
Type: single nucleotide variant
Location: chr4:186606167 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI <0.01 (gnomAD)
Residue 3418: the cadherin 31 domain

Full FAT1 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

FAT1 p.Ala1663Thr Uncertain significance ★★ same condition
FAT1 p.Ala1862Ser Uncertain significance ★★ ⚠ same condition
FAT1 p.Ala2046Thr Uncertain significance ★★ ⚠ same condition
FAT1 p.Ala2502Asp Uncertain significance ★★ ⚠ same condition
FAT1 p.Ala3007Val Uncertain significance ★★ same condition
FAT1 p.Ala3437Thr Uncertain significance ★★ ⚠ same condition
FAT1 p.Ala3913Ser Uncertain significance ★★ ⚠ same condition
FAT1 p.Ala4042Ser 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/fat1-p-pro3418leu (accessed [today's date]).

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