Is FAT2 p.Pro248Ser (c.742C>T) pathogenic?

FAT2 p.Pro248Ser (c.742C>T) is classified Benign/Likely benign in FAT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1199); Low-frequency (popmax 1.18%, eas).

How common is FAT2 p.Pro248Ser (c.742C>T) in the general population?

FAT2 p.Pro248Ser (c.742C>T) is low-frequency (popmax 1.18%, eas) (gnomAD).

What do computational predictors say about FAT2 p.Pro248Ser (c.742C>T)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

FAT2 p.Pro248Ser

c.742C>T · rs3734061 · VCV777597

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.18%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.082	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 6.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 28 kb · p 7.9e-10 · regional, not allelic
Overall
CADD	21.5	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 1.18% East Asian · 529/44,882 alleles

Filtering AF 1.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.06%

Overall 0.783% 12,641/1,613,950 alleles · low-frequency exomes 11,751/1,461,658 · genomes 890/152,292 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.18%	85
European (non-Finnish)	0.898%	111
Remaining individualsnot grpmax-eligible	0.808%	124
Finnishnot grpmax-eligible	0.453%	221
Admixed American	0.387%	259
South Asian	0.323%	310
Middle Eastern	0.264%	379
Ashkenazi Jewishnot grpmax-eligible	0.196%	510
African / African-American	0.159%	631

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.Pro248Ser
Coding: c.742C>T
MANE Select: NM_001447
dbSNP: rs3734061
Type: single nucleotide variant
Location: chr5:151568190 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)
Residue 248: the cadherin 2 domain; a UniProt-annotated variant site (in)

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

Similar variants

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
FAT2 p.Ala2618Thr 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-pro248ser (accessed [today's date]).

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