Is LDLR p.His407= (c.1221C>T) pathogenic?

LDLR p.His407= (c.1221C>T) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 7 submitters; last evaluated 2022-08-29). Very rare (popmax 0.00801%, afr); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.His407= (c.1221C>T)?

LDLR p.His407= (c.1221C>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.His407= (c.1221C>T) in the general population?

LDLR p.His407= (c.1221C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

LDLR p.His407=

c.1221C>T · rs778424518 · VCV430774

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 BP7 BP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.1221C>T (p.His407=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). BP4 - No REVEL, splicing evaluation required. Functional data not available A) not on limits B) does not create AG Variant not predicted to alter splicing BP7 - Variant is synonymous and meets BP4.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.57 · evaluated, not missing
Constraint at this position
Conservation	phyloP -9.1	GERP -5.1
Overall
CADD	5.302	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,884 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000682% 11/1,613,506 alleles · very rare exomes 7/1,461,418 · genomes 4/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,481
Admixed American	0.005%	19,987
European (non-Finnish)	0.000169%	590,019

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.His407=
Coding: c.1221C>T
MANE Select: NM_000527
dbSNP: rs778424518
Type: single nucleotide variant
Location: chr19:11113312 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 407: a β-strand

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

Disease context

hypercholesterolemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia

Similar variants

LDLR p.His407Gln Uncertain significance ★★ ⚠ same residue
LDLR p.His407fs Likely 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
LDLR c.190+4A>T Likely pathogenic ★★★ same condition
LDLR c.2140+1G>A 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-his407 (accessed [today's date]).

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