Is FLT4 p.Arg437Cys (c.1309C>T) pathogenic?

FLT4 p.Arg437Cys (c.1309C>T) is classified Uncertain significance in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely benign (0.2253); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with FLT4 p.Arg437Cys (c.1309C>T)?

FLT4 p.Arg437Cys (c.1309C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FLT4 p.Arg437Cys (c.1309C>T) in the general population?

FLT4 p.Arg437Cys (c.1309C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about FLT4 p.Arg437Cys (c.1309C>T)?

AlphaMissense predicts likely benign (score 0.2253) — an in-silico prediction, not a clinical call.

FLT4 p.Arg437Cys

c.1309C>T · VCV3279268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2253	likely benign
REVEL	0.381	indeterminate
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.13, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	24.1	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 0.004% African / African-American · 3/74,924 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00192% 31/1,612,652 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
European (non-Finnish)	0.0022%	45,383
Remaining individualsnot grpmax-eligible	0.0016%	62,464
South Asian	0.0011%	91,074

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.Arg437Cys
Coding: c.1309C>T
MANE Select: NM_182925
Type: single nucleotide variant
Location: chr5:180625981 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 437: a UniProt-annotated variant site (in chtd7); the ig-like c2-type 5 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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FLT4 p.Glu207Lys Uncertain significance ★★ ⚠ same condition
FLT4 p.Glu365Lys Uncertain significance ★★ ⚠ same condition
FLT4 p.Gly4Ala Uncertain significance ★★ ⚠ same condition
FLT4 p.Met1260Leu Uncertain significance ★★ ⚠ same condition
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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-arg437cys (accessed [today's date]).

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