Is FLT4 p.Arg472His (c.1415G>A) pathogenic?

FLT4 p.Arg472His (c.1415G>A) is classified Conflicting classifications of pathogenicity in FLT4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-08). AlphaMissense: likely benign (0.0712); Ultra-rare (popmax 0.0347%, afr); Associated with Inborn genetic diseases.

What condition is associated with FLT4 p.Arg472His (c.1415G>A)?

FLT4 p.Arg472His (c.1415G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FLT4 p.Arg472His (c.1415G>A) in the general population?

FLT4 p.Arg472His (c.1415G>A) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about FLT4 p.Arg472His (c.1415G>A)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

FLT4 p.Arg472His

c.1415G>A · rs143813005 · VCV2441523

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -6.87	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 0.81	GERP -1.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	19.33	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 0.0347% African / African-American · 26/74,994 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00329% 53/1,611,486 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,884
Middle Eastern	0.0196%	5,096
Remaining individualsnot grpmax-eligible	0.00962%	10,395
Admixed American	0.00667%	14,997
Finnishnot grpmax-eligible	0.00319%	31,386
East Asian	0.00223%	44,866
South Asian	0.0022%	45,505
European (non-Finnish)	0.000932%	107,261

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.Arg472His
Coding: c.1415G>A
MANE Select: NM_182925
dbSNP: rs143813005
Type: single nucleotide variant
Location: chr5:180625875 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 472: 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

Similar variants

FLT4 p.Gly1131Ser Pathogenic/Likely pathogenic ★★ same condition
FLT4 p.Ala702Ser Uncertain significance ★★ ⚠ same condition
FLT4 p.Arg1189His Uncertain significance ★★ ⚠ same condition
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
FLT4 p.Pro922Leu 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-arg472his (accessed [today's date]).

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