Is FAT1 p.Ala1663Thr (c.4987G>A) pathogenic?

FAT1 p.Ala1663Thr (c.4987G>A) is classified Uncertain significance in FAT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-02). AlphaMissense: likely benign (0.0905); Ultra-rare (popmax 0.0908%, afr); Associated with Inborn genetic diseases.

What condition is associated with FAT1 p.Ala1663Thr (c.4987G>A)?

FAT1 p.Ala1663Thr (c.4987G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FAT1 p.Ala1663Thr (c.4987G>A) in the general population?

FAT1 p.Ala1663Thr (c.4987G>A) is ultra-rare (popmax 0.0908%, afr) (gnomAD).

What do computational predictors say about FAT1 p.Ala1663Thr (c.4987G>A)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

FAT1 p.Ala1663Thr

c.4987G>A · rs200613891 · VCV3277769

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0908%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.303	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 97 kb · p 0.42 · regional, not allelic
Overall
CADD	21.0	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 0.0908% African / African-American · 68/74,914 alleles

Filtering AF 0.0734% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0671%

Overall 0.0062% 100/1,613,878 alleles · ultra-rare exomes 67/1,461,686 · genomes 33/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0908%	1,102
Middle Eastern	0.0164%	6,084
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0032%	31,232
European (non-Finnish)	0.00212%	47,196
South Asian	0.0011%	91,080

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.Ala1663Thr
Coding: c.4987G>A
MANE Select: NM_005245
dbSNP: rs200613891
Type: single nucleotide variant
Location: chr4:186621599 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI <0.01 (gnomAD)
Residue 1663: the cadherin 14 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.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
FAT1 p.Ala4224Gly 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-ala1663thr (accessed [today's date]).

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