Is FAT1 p.Ala225= (c.675G>A) pathogenic?

FAT1 p.Ala225= (c.675G>A) is classified Conflicting classifications of pathogenicity in FAT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-12). Rare (popmax 0.247%, eas); Associated with FAT1-related disorder.

What condition is associated with FAT1 p.Ala225= (c.675G>A)?

FAT1 p.Ala225= (c.675G>A) is associated with FAT1-related disorder (ClinVar).

How common is FAT1 p.Ala225= (c.675G>A) in the general population?

FAT1 p.Ala225= (c.675G>A) is rare (popmax 0.247%, eas) (gnomAD).

FAT1 p.Ala225=

c.675G>A · rs141154871 · VCV2629466

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.247%, eas)

Conditions

FAT1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.69, phastCons 1
Overall
CADD	14.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.247% East Asian · 111/44,870 alleles

Filtering AF 0.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.196%

Overall 0.0075% 121/1,613,934 alleles · rare exomes 108/1,461,692 · genomes 13/152,242 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.247%	404
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00267%	37,518
Admixed American	0.00167%	60,014
South Asian	0.0011%	91,072
European (non-Finnish)	0.000339%	294,968

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.Ala225=
Coding: c.675G>A
MANE Select: NM_005245
dbSNP: rs141154871
Type: single nucleotide variant
Location: chr4:186709153 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI <0.01 (gnomAD)
Residue 225: the cadherin 2 domain

Full FAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

FAT1-related disorder

Similar variants

FAT1 p.Ala225Val Likely benign ★ same residue
FAT1 p.Arg806His Uncertain significance ★★ ⚠ same condition
FAT1 p.Asn2666Ser Uncertain significance ★★ ⚠ same condition
FAT1 p.Asn710Ser Uncertain significance ★★ same condition
FAT1 p.Asn749His Uncertain significance ★★ same condition
FAT1 p.Asp1930His Uncertain significance ★★ same condition
FAT1 p.Gln958His Uncertain significance ★★ ⚠ same condition
FAT1 p.Glu1769Gly 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-ala225 (accessed [today's date]).

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