Is FAT4 p.Ser645Phe (c.1934C>T) pathogenic?

FAT4 p.Ser645Phe (c.1934C>T) is classified Uncertain significance in FAT4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-23). AlphaMissense: likely benign (0.1094); Very rare (popmax 0.00329%, sas); Associated with Hennekam lymphangiectasia-lymphedema syndrome 2.

What condition is associated with FAT4 p.Ser645Phe (c.1934C>T)?

FAT4 p.Ser645Phe (c.1934C>T) is associated with Hennekam lymphangiectasia-lymphedema syndrome 2, van Maldergem syndrome 2 (ClinVar).

How common is FAT4 p.Ser645Phe (c.1934C>T) in the general population?

FAT4 p.Ser645Phe (c.1934C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about FAT4 p.Ser645Phe (c.1934C>T)?

AlphaMissense predicts likely benign (score 0.1094) — an in-silico prediction, not a clinical call.

FAT4 p.Ser645Phe

c.1934C>T · rs1730741084 · VCV1374707

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1094	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.65, phastCons 0.026
Regional constraint	o/e 0.98	unconstrained · MANE · 175 kb · p 0.071 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000867% 14/1,614,214 alleles · very rare exomes 14/1,461,894 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
South Asiangrpmax	0.00329%	30,361
European (non-Finnish)	0.000339%	295,010

Ashkenazi Jewish 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.Ser645Phe
Coding: c.1934C>T
MANE Select: NM_001291303
dbSNP: rs1730741084
Type: single nucleotide variant
Location: chr4:125318345 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Residue 645: the cadherin 6 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.Ser645= 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-ser645phe (accessed [today's date]).

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