Is FLT1 p.Arg508Cys (c.1522C>T) pathogenic?

FLT1 p.Arg508Cys (c.1522C>T) is classified Uncertain significance in FLT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.2572); Ultra-rare (popmax 0.0485%, sas).

How common is FLT1 p.Arg508Cys (c.1522C>T) in the general population?

FLT1 p.Arg508Cys (c.1522C>T) is ultra-rare (popmax 0.0485%, sas) (gnomAD).

What do computational predictors say about FLT1 p.Arg508Cys (c.1522C>T)?

AlphaMissense predicts likely benign (score 0.2572) — an in-silico prediction, not a clinical call.

FLT1 p.Arg508Cys

c.1522C>T · VCV4668956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2572 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0485%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2572	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 173 kb · p 9.5e-14 · regional, not allelic
Overall
CADD	32.0	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 0.0485% South Asian · 44/90,788 alleles

Filtering AF 0.037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0331%

Overall 0.00406% 65/1,599,358 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0485%	2,063
Remaining individualsnot grpmax-eligible	0.00323%	31,002
Finnishnot grpmax-eligible	0.00158%	63,256
European (non-Finnish)	0.00154%	64,864

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: FLT1
Protein: p.Arg508Cys
Coding: c.1522C>T
MANE Select: NM_002019
Type: single nucleotide variant
Location: chr13:28405809 (GRCh38)
Gene constraint: LOEUF 0.379 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.86 · 12 PDB
Residue 508: a disulfide bond; the ig-like c2-type 5 domain

Full FLT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FLT1 p.Asp6Asn Benign ★★ same type
FLT1 p.Cys107= Likely benign ★★ same type
FLT1 p.Ile548Met Likely benign ★★ same type
FLT1 p.Leu492= Benign ★★ same type
FLT1 p.Met938Val Likely benign ★★ same type
FLT1 p.Pro1068= Benign ★★ same type
FLT1 p.Pro1201Leu Likely benign ★★ same type
FLT1 p.Thr260= Benign ★★ same type

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/flt1-p-arg508cys (accessed [today's date]).

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