Is VLDLR p.Phe643Val (c.1927T>G) pathogenic?

VLDLR p.Phe643Val (c.1927T>G) is classified Uncertain significance in VLDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-17). AlphaMissense: likely benign (0.2033); Absent from gnomAD v4.1; Associated with intellectual disability.

What condition is associated with VLDLR p.Phe643Val (c.1927T>G)?

VLDLR p.Phe643Val (c.1927T>G) is associated with intellectual disability (ClinVar).

How common is VLDLR p.Phe643Val (c.1927T>G) in the general population?

VLDLR p.Phe643Val (c.1927T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VLDLR p.Phe643Val (c.1927T>G)?

AlphaMissense predicts likely benign (score 0.2033) — an in-silico prediction, not a clinical call.

VLDLR p.Phe643Val

c.1927T>G · VCV4072109

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2033 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.2033	likely benign
REVEL	0.609	indeterminate
SaProt	LLR -4.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 0.8, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 32 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	26.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VLDLR
Protein: p.Phe643Val
Coding: c.1927T>G
MANE Select: NM_003383
Type: single nucleotide variant
Location: chr9:2648312 (GRCh38)
Gene constraint: LOEUF 0.828 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.12 · 27 PDB

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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VLDLR p.Arg301Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
VLDLR p.Gln232Glu Uncertain significance ★ ⚠ same condition
VLDLR c.2252-2A>C Likely pathogenic ★★ same type
VLDLR c.449-2A>T Likely pathogenic ★★ same type
VLDLR c.83-1G>A Pathogenic/Likely pathogenic ★★ same type
VLDLR p.Arg279Ter Pathogenic ★★ same type
VLDLR p.Arg301Ter Pathogenic ★★ same type
VLDLR p.Trp529Ter Pathogenic ★★ 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/vldlr-p-phe643val (accessed [today's date]).

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