Is FAT4 p.Val367Ile (c.1099G>A) pathogenic?

FAT4 p.Val367Ile (c.1099G>A) is classified Conflicting classifications of pathogenicity in FAT4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.2823); Ultra-rare (popmax 0.0362%, nfe); Associated with Hennekam lymphangiectasia-lymphedema syndrome 2.

What condition is associated with FAT4 p.Val367Ile (c.1099G>A)?

FAT4 p.Val367Ile (c.1099G>A) is associated with Hennekam lymphangiectasia-lymphedema syndrome 2, van Maldergem syndrome 2 (ClinVar).

How common is FAT4 p.Val367Ile (c.1099G>A) in the general population?

FAT4 p.Val367Ile (c.1099G>A) is ultra-rare (popmax 0.0362%, nfe) (gnomAD).

What do computational predictors say about FAT4 p.Val367Ile (c.1099G>A)?

AlphaMissense predicts likely benign (score 0.2823) — an in-silico prediction, not a clinical call.

FAT4 p.Val367Ile

c.1099G>A · rs747531733 · VCV993351

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 2

Computational evidence

Protein change
AlphaMissense	0.2823	likely benign
REVEL	0.194	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 175 kb · p 0.071 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0362% European (non-Finnish) · 427/1,180,028 alleles

Filtering AF 0.0333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0322%

Overall 0.031% 501/1,613,742 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.106%	947
European (non-Finnish)grpmax	0.0362%	2,764
African / African-American	0.00934%	10,705
Finnishnot grpmax-eligible	0.00157%	63,712

Remaining individuals 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: FAT4
Protein: p.Val367Ile
Coding: c.1099G>A
MANE Select: NM_001291303
dbSNP: rs747531733
Type: single nucleotide variant
Location: chr4:125317510 (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

Hennekam lymphangiectasia-lymphedema syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: van Maldergem syndrome 2

Similar variants

FAT4 p.Val367= Benign/Likely benign ★★ 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-val367ile (accessed [today's date]).

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