Is FAT4 p.Val367= (c.1101A>G) pathogenic?

FAT4 p.Val367= (c.1101A>G) is classified Benign/Likely benign in FAT4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-26). Low-frequency (popmax 4.81%, afr); Associated with van Maldergem syndrome 2.

What condition is associated with FAT4 p.Val367= (c.1101A>G)?

FAT4 p.Val367= (c.1101A>G) is associated with van Maldergem syndrome 2, Hennekam lymphangiectasia-lymphedema syndrome 2 (ClinVar).

How common is FAT4 p.Val367= (c.1101A>G) in the general population?

FAT4 p.Val367= (c.1101A>G) is low-frequency (popmax 4.81%, afr) (gnomAD).

FAT4 p.Val367=

c.1101A>G · rs57692448 · VCV384624

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.81%, afr)

Conditions

van Maldergem syndrome 2

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 -2	GERP -4.4
Overall
CADD	0.849	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.81% African / African-American · 3,610/75,040 alleles

Filtering AF 4.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.63%

Overall 0.271% 4,380/1,613,876 alleles · low-frequency exomes 2,282/1,461,570 · genomes 2,098/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.81%	21
Middle Eastern	0.709%	141
Remaining individualsnot grpmax-eligible	0.389%	257
Admixed American	0.36%	278
European (non-Finnish)	0.0218%	4,592
South Asian	0.0121%	8,281

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: FAT4
Protein: p.Val367=
Coding: c.1101A>G
MANE Select: NM_001291303
dbSNP: rs57692448
Type: single nucleotide variant
Location: chr4:125317512 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Residue 367: a β-strand; the cadherin 4 domain

Full FAT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

van Maldergem syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hennekam lymphangiectasia-lymphedema syndrome 2

Similar variants

FAT4 p.Val367Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
FAT4 p.Arg1902Ter Pathogenic/Likely pathogenic ★★ same condition
FAT4 p.Gln4530Ter Pathogenic/Likely pathogenic ★★ same condition
FAT4 c.5307+6T>A Uncertain significance ★★ same condition
FAT4 c.6843+4A>G Uncertain significance ★★ same condition
FAT4 p.Ala132Asp Uncertain significance ★★ ⚠ same condition
FAT4 p.Ala1984Thr Uncertain significance ★★ ⚠ same condition
FAT4 p.Ala198Val 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/fat4-p-val367 (accessed [today's date]).

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