Is FAT2 p.Pro263Ser (c.787C>T) pathogenic?

FAT2 p.Pro263Ser (c.787C>T) is classified Uncertain significance in FAT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0686); Ultra-rare (popmax 0.0461%, sas).

How common is FAT2 p.Pro263Ser (c.787C>T) in the general population?

FAT2 p.Pro263Ser (c.787C>T) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

What do computational predictors say about FAT2 p.Pro263Ser (c.787C>T)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

FAT2 p.Pro263Ser

c.787C>T · rs549767297 · VCV2969212

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.06	GERP -4.3
Regional constraint	o/e 0.90	unconstrained · MANE · 28 kb · p 7.9e-10 · regional, not allelic
Overall
CADD	6.033	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0461% South Asian · 42/91,082 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00266% 43/1,614,154 alleles · ultra-rare exomes 41/1,461,868 · genomes 2/152,286 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,169
Remaining individualsnot grpmax-eligible	0.0016%	62,512

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: FAT2
Protein: p.Pro263Ser
Coding: c.787C>T
MANE Select: NM_001447
dbSNP: rs549767297
Type: single nucleotide variant
Location: chr5:151568145 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)

Full FAT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FAT2 p.Pro263= Benign ★ same residue
FAT2 p.Ala1009Val Uncertain significance ★★ ⚠ same type
FAT2 p.Ala1078Thr Uncertain significance ★★ ⚠ same type
FAT2 p.Ala1079Asp Uncertain significance ★★ ⚠ same type
FAT2 p.Ala1975Glu Uncertain significance ★★ same type
FAT2 p.Ala2491Glu Uncertain significance ★★ same type
FAT2 p.Ala249Val Uncertain significance ★★ ⚠ same type
FAT2 p.Ala2587Val 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/fat2-p-pro263ser (accessed [today's date]).

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