Is FLT4 p.Ser565Phe (c.1694C>T) pathogenic?

FLT4 p.Ser565Phe (c.1694C>T) is classified Uncertain significance in FLT4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-10). AlphaMissense: likely benign (0.1707); Very rare (popmax 0.00223%, eas); Associated with lymphatic malformation 1.

What condition is associated with FLT4 p.Ser565Phe (c.1694C>T)?

FLT4 p.Ser565Phe (c.1694C>T) is associated with lymphatic malformation 1 (ClinVar).

How common is FLT4 p.Ser565Phe (c.1694C>T) in the general population?

FLT4 p.Ser565Phe (c.1694C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Milroy disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FLT4 p.Ser565Phe (c.1694C>T)?

AlphaMissense predicts likely benign (score 0.1707) — an in-silico prediction, not a clinical call.

FLT4 p.Ser565Phe

c.1694C>T · VCV4082924

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1707 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lymphatic malformation 1

Computational evidence

Protein change
AlphaMissense	0.1707	likely benign
REVEL	0.331	indeterminate
SaProt	LLR -9.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	23.5	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Overall 6.84e-05% 1/1,461,210 alleles · very rare

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: FLT4
Protein: p.Ser565Phe
Coding: c.1694C>T
MANE Select: NM_182925
Type: single nucleotide variant
Location: chr5:180621868 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 565: the ig-like c2-type 6 domain; a UniProt-annotated variant site (in chtd7)

Full FLT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lymphatic malformation 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Milroy disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Antenatal, Infancy, Neonatal

Similar variants

FLT4 p.Arg1041Gln Pathogenic/Likely pathogenic ★★ same condition
FLT4 p.Arg1041Trp Pathogenic/Likely pathogenic ★★ same condition
FLT4 p.Gly857Arg Pathogenic ★★ same condition
FLT4 p.Pro1137Leu Likely pathogenic ★★ same condition
FLT4 p.Ala702Ser Uncertain significance ★★ ⚠ same condition
FLT4 p.Ala855Thr Uncertain significance ★★ ⚠ same condition
FLT4 p.Arg1060Gln Uncertain significance ★★ ⚠ same condition
FLT4 p.Arg1070Cys 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/flt4-p-ser565phe (accessed [today's date]).

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