Is FLT4 p.Arg1070Cys (c.3208C>T) pathogenic?

FLT4 p.Arg1070Cys (c.3208C>T) is classified Uncertain significance in FLT4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-09). AlphaMissense: likely pathogenic (0.5654); Ultra-rare (popmax 0.0164%, mid); Associated with lymphatic malformation 1.

What condition is associated with FLT4 p.Arg1070Cys (c.3208C>T)?

FLT4 p.Arg1070Cys (c.3208C>T) is associated with lymphatic malformation 1 (ClinVar).

How common is FLT4 p.Arg1070Cys (c.3208C>T) in the general population?

FLT4 p.Arg1070Cys (c.3208C>T) is ultra-rare (popmax 0.0164%, 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.Arg1070Cys (c.3208C>T)?

AlphaMissense predicts likely pathogenic (score 0.5654) — an in-silico prediction, not a clinical call.

FLT4 p.Arg1070Cys

c.3208C>T · rs774554521 · VCV1331243

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5654 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphatic malformation 1

Computational evidence

Protein change
AlphaMissense	0.5654	likely pathogenic
REVEL	0.748	pathogenic-leaning
SaProt	LLR -13.28	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 7.1	GERP -3.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00105% 17/1,613,822 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00267%	37,461
Finnishnot grpmax-eligible	0.00157%	63,836
European (non-Finnish)	0.0011%	90,770

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.Arg1070Cys
Coding: c.3208C>T
MANE Select: NM_182925
dbSNP: rs774554521
Type: single nucleotide variant
Location: chr5:180616378 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 1070: 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.Arg1070Leu Uncertain significance ★ ⚠ same residue
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

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-arg1070cys (accessed [today's date]).

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