Is FLT4 p.Glu76Lys (c.226G>A) pathogenic?

FLT4 p.Glu76Lys (c.226G>A) is classified Likely benign in FLT4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-03-25). AlphaMissense: likely benign (0.0671); Low-frequency (popmax 1.42%, sas); Associated with FLT4-related disorder.

What condition is associated with FLT4 p.Glu76Lys (c.226G>A)?

FLT4 p.Glu76Lys (c.226G>A) is associated with FLT4-related disorder (ClinVar).

How common is FLT4 p.Glu76Lys (c.226G>A) in the general population?

FLT4 p.Glu76Lys (c.226G>A) is low-frequency (popmax 1.42%, sas) (gnomAD).

What do computational predictors say about FLT4 p.Glu76Lys (c.226G>A)?

AlphaMissense predicts likely benign (score 0.0671) — an in-silico prediction, not a clinical call.

FLT4 p.Glu76Lys

c.226G>A · rs202015753 · VCV3045299

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0671 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.42%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FLT4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0671	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.02	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 1.1	GERP -0.97, phastCons 0.54
Regional constraint	o/e 0.88	unconstrained · MANE · 19 kb · p 0.1 · regional, not allelic
Overall
CADD	17.59	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 1.42% South Asian · 1,289/91,070 alleles

Filtering AF 1.35% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.33%

Overall 0.0859% 1,385/1,611,686 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.42%	71
Middle Eastern	0.182%	551
Remaining individualsnot grpmax-eligible	0.0656%	1,524
African / African-American	0.0147%	6,821
East Asian	0.00669%	14,955
Admixed American	0.00333%	30,008
European (non-Finnish)	0.00229%	43,702
Finnishnot grpmax-eligible	0.00162%	61,716

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.Glu76Lys
Coding: c.226G>A
MANE Select: NM_182925
dbSNP: rs202015753
Type: single nucleotide variant
Location: chr5:180630729 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 76: a disulfide bond; the ig-like c2-type 1 domain

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

Disease context

FLT4-related disorder

Similar variants

FLT4 p.Gly857Arg Pathogenic ★★ same condition
FLT4 p.Pro1137Leu Likely pathogenic ★★ same condition
FLT4 p.Ser393Arg Uncertain significance ★★ ⚠ same condition
FLT4 c.2168-1G>A Likely pathogenic ★ same condition
FLT4 p.Arg1041Gly Likely pathogenic ★ same condition
FLT4 p.Gln1020Leu Pathogenic ★ same condition
FLT4 p.Gln1179Ter Pathogenic ★ same condition
FLT4 p.Gly1276Glu Likely pathogenic ★ 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-glu76lys (accessed [today's date]).

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