Is LDLR p.Cys677Arg (c.2029T>C) pathogenic?

LDLR p.Cys677Arg (c.2029T>C) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-07-16). AlphaMissense: likely pathogenic (0.9951); Very rare (popmax 0.000424%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with LDLR p.Cys677Arg (c.2029T>C)?

LDLR p.Cys677Arg (c.2029T>C) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys677Arg (c.2029T>C) in the general population?

LDLR p.Cys677Arg (c.2029T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Cys677Arg (c.2029T>C)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

LDLR p.Cys677Arg

c.2029T>C · rs775092314 · VCV226384

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic ✓ concordant with ClinVar · top 3% in LDLR
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -14.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	26.7	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 0.000424% European (non-Finnish) · 5/1,180,050 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,082 alleles · very rare exomes 5/1,461,848 · genomes 1/152,234 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)grpmax	0.000424%	236,010

Remaining individuals 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: LDLR
Protein: p.Cys677Arg
Coding: c.2029T>C
MANE Select: NM_000527
dbSNP: rs775092314
Type: single nucleotide variant
Location: chr19:11120411 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 677: the egf-like 3 domain; a UniProt-annotated variant site (in fhcl1; new york-3); a disulfide bond

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1 homozygous familial hypercholesterolemia

Similar variants

LDLR p.Cys677Phe Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys677Ter Pathogenic ★★ same residue
LDLR p.Cys677Tyr Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys677fs Pathogenic ★★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A Pathogenic ★★★ same condition
LDLR c.1359-5C>G Likely pathogenic ★★★ same condition
LDLR c.1705+2T>C Likely pathogenic ★★★ 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/ldlr-p-cys677arg (accessed [today's date]).

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