Is FLT4 p.Pro1077Ser (c.3229C>T) pathogenic?

FLT4 p.Pro1077Ser (c.3229C>T) is classified Likely pathogenic in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-25). AlphaMissense: likely pathogenic (0.986); Absent from gnomAD v4.1; Associated with lymphatic malformation 1.

What condition is associated with FLT4 p.Pro1077Ser (c.3229C>T)?

FLT4 p.Pro1077Ser (c.3229C>T) is associated with lymphatic malformation 1 (ClinVar).

How common is FLT4 p.Pro1077Ser (c.3229C>T) in the general population?

FLT4 p.Pro1077Ser (c.3229C>T) is absent from gnomAD v4.1 (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.Pro1077Ser (c.3229C>T)?

AlphaMissense predicts likely pathogenic (score 0.986) — an in-silico prediction, not a clinical call.

FLT4 p.Pro1077Ser

c.3229C>T · VCV4818881

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphatic malformation 1

Computational evidence

Protein change
AlphaMissense	0.986	likely pathogenic ✓ concordant with ClinVar · top 6% in FLT4
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -15.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.22	constrained · MANE · 1,134 bp · p 1.2e-11 · regional, not allelic
Overall
CADD	32.0	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

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: FLT4
Protein: p.Pro1077Ser
Coding: c.3229C>T
MANE Select: NM_182925
Type: single nucleotide variant
Location: chr5:180614170 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 1077: the protein kinase 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-pro1077ser (accessed [today's date]).

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