Is FAT1 p.Pro2248= (c.6744G>A) pathogenic?

FAT1 p.Pro2248= (c.6744G>A) is classified Benign in FAT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Common (popmax 6.83%, mid) — too common for a highly-penetrant pathogenic allele.

FAT1 p.Pro2248=

Q: How common is FAT1 p.Pro2248= (c.6744G>A) in the general population?

FAT1 p.Pro2248= (c.6744G>A) is common (popmax 6.83%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6744G>A · rs11931107 · VCV1227435

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 6.83%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.9	GERP -3.8
Overall
CADD	1.421	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.83% Middle Eastern · 414/6,062 alleles

Filtering AF 6.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.07%

Overall 5.76% 92,905/1,613,850 alleles · common exomes 84,554/1,461,698 · genomes 8,351/152,152 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	8.66%	12
Middle Easterngrpmax	6.83%	15
Ashkenazi Jewishnot grpmax-eligible	6.62%	15
European (non-Finnish)	5.89%	17
Remaining individualsnot grpmax-eligible	5.66%	18
South Asian	5.47%	18
Amishnot grpmax-eligible	4.5%	22
African / African-American	4.48%	22
Admixed American	3.49%	29
East Asian	3.33%	30

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro2248=
Coding: c.6744G>A
MANE Select: NM_005245
dbSNP: rs11931107
Type: single nucleotide variant
Location: chr4:186619842 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI <0.01 (gnomAD)
Residue 2248: the cadherin 20 domain

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

Similar variants

FAT1 p.Pro2248Leu Uncertain significance ★★ same residue
FAT1 p.Ala1663Thr Uncertain significance ★★ same type
FAT1 p.Ala1762Val Uncertain significance ★★ ⚠ same type
FAT1 p.Ala1862Ser Uncertain significance ★★ ⚠ same type
FAT1 p.Ala2046Thr Uncertain significance ★★ ⚠ same type
FAT1 p.Ala2456Thr Uncertain significance ★★ ⚠ same type
FAT1 p.Ala2502Asp Uncertain significance ★★ ⚠ same type
FAT1 p.Ala3007Val 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/fat1-p-pro2248 (accessed [today's date]).

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