Is FAT2 p.Val3519= (c.10557C>G) pathogenic?

FAT2 p.Val3519= (c.10557C>G) is classified Benign in FAT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Common (popmax 20.3%, nfe) — too common for a highly-penetrant pathogenic allele.

FAT2 p.Val3519=

Q: How common is FAT2 p.Val3519= (c.10557C>G) in the general population?

FAT2 p.Val3519= (c.10557C>G) is common (popmax 20.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.10557C>G · rs3734047 · VCV1251356

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 20.3%, nfe) — 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.
REVEL	0.257	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -4, phastCons 0.84
Overall
CADD	0.129	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 20.3% European (non-Finnish) · 238,338/1,173,778 alleles

Filtering AF 20.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.2%

Overall 18.3% 293,462/1,606,800 alleles · common exomes 271,221/1,454,568 · genomes 22,241/152,232 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	30.8%	3
Ashkenazi Jewishnot grpmax-eligible	21.4%	5
European (non-Finnish)grpmax	20.3%	5
Middle Eastern	20.2%	5
Remaining individualsnot grpmax-eligible	18.2%	5
Admixed American	16.4%	6
Finnishnot grpmax-eligible	16.1%	6
East Asian	13.3%	8
South Asian	7.95%	13
African / African-American	3.51%	28

Amish 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: FAT2
Protein: p.Val3519=
Coding: c.10557C>G
MANE Select: NM_001447
dbSNP: rs3734047
Type: single nucleotide variant
Location: chr5:151522036 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)
Residue 3519: the cadherin 31 domain

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-val3519 (accessed [today's date]).

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