Is FAT4 p.Ser3237Pro (c.9709T>C) pathogenic?

FAT4 p.Ser3237Pro (c.9709T>C) is classified Uncertain significance in FAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-24). AlphaMissense: likely pathogenic (0.7195); Absent from gnomAD v4.1; Associated with Hennekam lymphangiectasia-lymphedema syndrome 2.

What condition is associated with FAT4 p.Ser3237Pro (c.9709T>C)?

FAT4 p.Ser3237Pro (c.9709T>C) is associated with Hennekam lymphangiectasia-lymphedema syndrome 2, van Maldergem syndrome 2 (ClinVar).

How common is FAT4 p.Ser3237Pro (c.9709T>C) in the general population?

FAT4 p.Ser3237Pro (c.9709T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FAT4 p.Ser3237Pro (c.9709T>C)?

AlphaMissense predicts likely pathogenic (score 0.7195) — an in-silico prediction, not a clinical call.

FAT4 p.Ser3237Pro

c.9709T>C · VCV3590050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7195 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 2

Computational evidence

Protein change
AlphaMissense	0.7195	likely pathogenic
REVEL	0.146	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.54, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 175 kb · p 0.071 · regional, not allelic
Overall
CADD	19.89	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S3235P vs ClinVar S3237P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FAT4
Protein: p.Ser3237Pro
Coding: c.9709T>C
MANE Select: NM_001291303
Type: single nucleotide variant
Location: chr4:125450719 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)

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.Ser3237= 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-ser3237pro (accessed [today's date]).

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