Is FLT4 p.Ala67Val (c.200C>T) pathogenic?

FLT4 p.Ala67Val (c.200C>T) is classified Uncertain significance in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). AlphaMissense: likely benign (0.0648); Ultra-rare (popmax 0.0329%, mid); Associated with lymphatic malformation 1.

What condition is associated with FLT4 p.Ala67Val (c.200C>T)?

FLT4 p.Ala67Val (c.200C>T) is associated with lymphatic malformation 1, capillary infantile hemangioma, congenital heart defects, multiple types, 7 (ClinVar).

How common is FLT4 p.Ala67Val (c.200C>T) in the general population?

FLT4 p.Ala67Val (c.200C>T) is ultra-rare (popmax 0.0329%, mid) (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.Ala67Val (c.200C>T)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

FLT4 p.Ala67Val

c.200C>T · VCV3892328

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphatic malformation 1

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -2.7
Regional constraint	o/e 0.88	unconstrained · MANE · 19 kb · p 0.1 · regional, not allelic
Overall
CADD	6.639	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00342% 55/1,608,604 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
Admixed American	0.00834%	11,994
South Asian	0.00439%	22,760
European (non-Finnish)	0.00356%	28,088
Remaining individualsnot grpmax-eligible	0.0032%	31,212

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.Ala67Val
Coding: c.200C>T
MANE Select: NM_182925
Type: single nucleotide variant
Location: chr5:180630755 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 67: a disulfide bond; the ig-like c2-type 1 domain

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

Also linked: capillary infantile hemangioma congenital heart defects, multiple types, 7

For Milroy disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Antenatal, Infancy, Neonatal

Similar variants

FLT4 p.Ala67= Likely benign ★ same residue
FLT4 p.Arg1041Gln Pathogenic/Likely pathogenic ★★ same condition
FLT4 p.Arg1041Trp Pathogenic/Likely pathogenic ★★ same condition
FLT4 p.Arg318Ter 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

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-ala67val (accessed [today's date]).

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