Is FAT4 p.Pro415Arg (c.1244C>G) pathogenic?

FAT4 p.Pro415Arg (c.1244C>G) is classified Conflicting classifications of pathogenicity in FAT4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-08-14). AlphaMissense: likely pathogenic (0.628); Rare (popmax 0.417%, eas); Associated with van Maldergem syndrome 2.

What condition is associated with FAT4 p.Pro415Arg (c.1244C>G)?

FAT4 p.Pro415Arg (c.1244C>G) is associated with van Maldergem syndrome 2, Hennekam lymphangiectasia-lymphedema syndrome 2 (ClinVar).

How common is FAT4 p.Pro415Arg (c.1244C>G) in the general population?

FAT4 p.Pro415Arg (c.1244C>G) is rare (popmax 0.417%, eas) (gnomAD).

What do computational predictors say about FAT4 p.Pro415Arg (c.1244C>G)?

AlphaMissense predicts likely pathogenic (score 0.628) — an in-silico prediction, not a clinical call.

FAT4 p.Pro415Arg

c.1244C>G · rs746792200 · VCV1112797

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.628 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.417%, eas)

Conditions

van Maldergem syndrome 2

Computational evidence

Protein change
AlphaMissense	0.628	likely pathogenic
REVEL	0.311	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 175 kb · p 0.071 · regional, not allelic
Overall
CADD	31.0	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 0.417% East Asian · 187/44,870 alleles

Filtering AF 0.368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.349%

Overall 0.012% 194/1,613,890 alleles · rare exomes 183/1,461,758 · genomes 11/152,132 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.417%	240
Remaining individualsnot grpmax-eligible	0.0032%	31,245
Admixed American	0.00167%	60,000
Finnishnot grpmax-eligible	0.00156%	63,968
South Asian	0.0011%	91,036
European (non-Finnish)	0.000169%	590,005

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.Pro415Arg
Coding: c.1244C>G
MANE Select: NM_001291303
dbSNP: rs746792200
Type: single nucleotide variant
Location: chr4:125317655 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Residue 415: 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.Pro415= 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-pro415arg (accessed [today's date]).

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