Is FLT4 p.Pro641Ser (c.1921C>T) pathogenic?

FLT4 p.Pro641Ser (c.1921C>T) is classified Benign/Likely benign in FLT4 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0972); Rare (popmax 0.64%, nfe); Associated with colon carcinoma.

What condition is associated with FLT4 p.Pro641Ser (c.1921C>T)?

FLT4 p.Pro641Ser (c.1921C>T) is associated with colon carcinoma (ClinVar).

How common is FLT4 p.Pro641Ser (c.1921C>T) in the general population?

FLT4 p.Pro641Ser (c.1921C>T) is rare (popmax 0.64%, nfe) (gnomAD).

What do computational predictors say about FLT4 p.Pro641Ser (c.1921C>T)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

FLT4 p.Pro641Ser

c.1921C>T · rs55667289 · VCV263032

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.64%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

colon carcinoma

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -6.37	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 8.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	21.4	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 0.64% European (non-Finnish) · 7,522/1,175,430 alleles

Filtering AF 0.628% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.623%

Overall 0.528% 8,487/1,606,982 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.34%	75
European (non-Finnish)grpmax	0.64%	156
Remaining individualsnot grpmax-eligible	0.439%	228
Finnishnot grpmax-eligible	0.22%	454
Admixed American	0.139%	721
Amishnot grpmax-eligible	0.11%	912
African / African-American	0.0854%	1,171
Middle Eastern	0.0828%	1,208
South Asian	0.0077%	12,979

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro641Ser
Coding: c.1921C>T
MANE Select: NM_182925
dbSNP: rs55667289
Type: single nucleotide variant
Location: chr5:180621641 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 641: the ig-like c2-type 6 domain; a disulfide bond; a UniProt-annotated variant site (in chtd7); a UniProt-annotated variant site (in)

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

Disease context

colon carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FLT4 p.Ala702Ser Uncertain significance ★★ ⚠ same condition
FLT4 c.2407-7C>T Uncertain significance same condition
FLT4 c.2542+12A>G Uncertain significance same condition
FLT4 c.3002-9A>C Uncertain significance same condition
FLT4 p.Ala1022Val Uncertain significance ⚠ same condition
FLT4 p.Asp834Glu Uncertain significance ⚠ same condition
FLT4 p.Gly811= Uncertain significance same condition
FLT4 p.Leu824Met 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-pro641ser (accessed [today's date]).

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