Is KDR p.Leu462Val (c.1384T>G) pathogenic?

KDR p.Leu462Val (c.1384T>G) is classified Benign/Likely benign in KDR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-02-01). AlphaMissense: likely benign (0.1123); Rare (popmax 0.217%, nfe).

How common is KDR p.Leu462Val (c.1384T>G) in the general population?

KDR p.Leu462Val (c.1384T>G) is rare (popmax 0.217%, nfe) (gnomAD).

What do computational predictors say about KDR p.Leu462Val (c.1384T>G)?

AlphaMissense predicts likely benign (score 0.1123) — an in-silico prediction, not a clinical call.

KDR p.Leu462Val

c.1384T>G · rs56286620 · VCV134602

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1123 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.217%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1123	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -7.33	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 -0.14	GERP -4.8, phastCons 0.017
Regional constraint	o/e 0.94	unconstrained · MANE · 23 kb · p 0.092 · regional, not allelic
Overall
CADD	13.42	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 0.217% European (non-Finnish) · 2,565/1,179,902 alleles

Filtering AF 0.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.207%

Overall 0.187% 3,022/1,613,950 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.43%	70
Finnishnot grpmax-eligible	0.526%	190
European (non-Finnish)grpmax	0.217%	460
Remaining individualsnot grpmax-eligible	0.096%	1,041
African / African-American	0.04%	2,501
Admixed American	0.0267%	3,751
South Asian	0.0011%	91,072

Amish 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: KDR
Protein: p.Leu462Val
Coding: c.1384T>G
MANE Select: NM_002253
dbSNP: rs56286620
Type: single nucleotide variant
Location: chr4:55107765 (GRCh38)
Gene constraint: LOEUF 0.328 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.67 · 54 PDB
Residue 462: a β-strand; a disulfide bond; a UniProt-annotated variant site (in); the ig-like c2-type 5 domain

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

Similar variants

KDR p.Ala379Val Uncertain significance ★★ ⚠ same type
KDR p.Ala757Gly Uncertain significance ★★ ⚠ same type
KDR p.Asp832His Uncertain significance ★★ ⚠ same type
KDR p.Val416Ala Uncertain significance ★★ ⚠ same type
KDR p.Ala1030= Benign ★★ same type
KDR p.Ala532= Benign ★★ same type
KDR p.Arg842His Likely benign ★★ ⚠ same type
KDR p.Cys482Arg Likely 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/kdr-p-leu462val (accessed [today's date]).

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