Is FLT4 p.Asn218Ser (c.653A>G) pathogenic?

FLT4 p.Asn218Ser (c.653A>G) is classified Uncertain significance in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.063); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with FLT4 p.Asn218Ser (c.653A>G)?

FLT4 p.Asn218Ser (c.653A>G) is associated with Inborn genetic diseases (ClinVar).

How common is FLT4 p.Asn218Ser (c.653A>G) in the general population?

FLT4 p.Asn218Ser (c.653A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about FLT4 p.Asn218Ser (c.653A>G)?

AlphaMissense predicts likely benign (score 0.063) — an in-silico prediction, not a clinical call.

FLT4 p.Asn218Ser

c.653A>G · rs1763960046 · VCV2221149

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.063	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -2.84	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 -0.43, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 1,607 bp · p 1.9e-12 · regional, not allelic
Overall
CADD	8.786	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 0.0011% South Asian · 1/91,054 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,460,552 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,054
European (non-Finnish)	0.000509%	196,654

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.Asn218Ser
Coding: c.653A>G
MANE Select: NM_182925
dbSNP: rs1763960046
Type: single nucleotide variant
Location: chr5:180629966 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 218: a UniProt-annotated variant site (in chtd7)

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-asn218ser (accessed [today's date]).

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