Is FLT4 p.Arg476Trp (c.1426C>T) pathogenic?

FLT4 p.Arg476Trp (c.1426C>T) is classified Uncertain significance in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1181); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with FLT4 p.Arg476Trp (c.1426C>T)?

FLT4 p.Arg476Trp (c.1426C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FLT4 p.Arg476Trp (c.1426C>T) in the general population?

FLT4 p.Arg476Trp (c.1426C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about FLT4 p.Arg476Trp (c.1426C>T)?

AlphaMissense predicts likely benign (score 0.1181) — an in-silico prediction, not a clinical call.

FLT4 p.Arg476Trp

c.1426C>T · VCV4620084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1181 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1181	likely benign
REVEL	0.48	indeterminate
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -2.6, phastCons 0.09
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	21.6	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 0.0133% Admixed American · 8/59,990 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000993% 16/1,611,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
East Asian	0.00668%	14,961
South Asian	0.00329%	30,361
African / African-American	0.00133%	74,920
European (non-Finnish)	8.48e-05%	1,179,916

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.Arg476Trp
Coding: c.1426C>T
MANE Select: NM_182925
Type: single nucleotide variant
Location: chr5:180624057 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 476: a disulfide bond; 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

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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-arg476trp (accessed [today's date]).

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