Is FLT4 p.Arg1319Trp (c.3955C>T) pathogenic?

FLT4 p.Arg1319Trp (c.3955C>T) is classified Conflicting classifications of pathogenicity in FLT4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-25). AlphaMissense: likely benign (0.0808); Ultra-rare (popmax 0.0661%, mid); Associated with lymphatic malformation 1.

What condition is associated with FLT4 p.Arg1319Trp (c.3955C>T)?

FLT4 p.Arg1319Trp (c.3955C>T) is associated with lymphatic malformation 1 (ClinVar).

How common is FLT4 p.Arg1319Trp (c.3955C>T) in the general population?

FLT4 p.Arg1319Trp (c.3955C>T) is ultra-rare (popmax 0.0661%, 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.Arg1319Trp (c.3955C>T)?

AlphaMissense predicts likely benign (score 0.0808) — an in-silico prediction, not a clinical call.

FLT4 p.Arg1319Trp

c.3955C>T · VCV3279264

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0808 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphatic malformation 1

Computational evidence

Protein change
AlphaMissense	0.0808	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -8.57	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 0.71	GERP -3
Regional constraint	o/e 0.95	unconstrained · MANE · 9,843 bp · p 0.36 · regional, not allelic
Overall
CADD	16.84	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

Grpmax group 0.0661% Middle Eastern · 4/6,048 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00341% 55/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,512
South Asian	0.022%	4,551
East Asian	0.0111%	8,976
African / African-American	0.0107%	9,383
Admixed American	0.005%	20,002
Remaining individualsnot grpmax-eligible	0.0048%	20,828
Finnishnot grpmax-eligible	0.00313%	31,993
European (non-Finnish)	0.000848%	117,991

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.Arg1319Trp
Coding: c.3955C>T
MANE Select: NM_182925
Type: single nucleotide variant
Location: chr5:180603329 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 1319: the 'disordered' region; 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-arg1319trp (accessed [today's date]).

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