Is LDLR p.Pro608Ser (c.1822C>T) pathogenic?

LDLR p.Pro608Ser (c.1822C>T) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.8909); Very rare (popmax 0.000169%, nfe); Associated with LDLR-related disorder.

What condition is associated with LDLR p.Pro608Ser (c.1822C>T)?

LDLR p.Pro608Ser (c.1822C>T) is associated with LDLR-related disorder, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Pro608Ser (c.1822C>T) in the general population?

LDLR p.Pro608Ser (c.1822C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Pro608Ser (c.1822C>T)?

AlphaMissense predicts likely pathogenic (score 0.8909) — an in-silico prediction, not a clinical call.

LDLR p.Pro608Ser

c.1822C>T · rs879255034 · VCV252049

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

LDLR-related disorder

Computational evidence

Protein change
AlphaMissense	0.8909	likely pathogenic ✓ concordant with ClinVar
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -12.46	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 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	26.2	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 0.000169% European (non-Finnish) · 2/1,180,024 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,962 alleles · very rare exomes 1/1,461,882 · genomes 1/152,080 · joint denominator

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.Pro608Ser
Coding: c.1822C>T
MANE Select: NM_000527
dbSNP: rs879255034
Type: single nucleotide variant
Location: chr19:11116975 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 608: a UniProt-annotated variant site (in fhcl1); a β-strand

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

Disease context

LDLR-related disorder

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1

Similar variants

LDLR p.Pro608Arg Likely pathogenic ★★ same residue
LDLR p.Pro608His Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Pro608Leu Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Pro608Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
LDLR p.Pro608= Likely benign ★ 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

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-pro608ser (accessed [today's date]).

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