Is LRP12 p.Ala554Ser (c.1660G>T) pathogenic?

LRP12 p.Ala554Ser (c.1660G>T) is classified Uncertain significance in LRP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.2614); Rare (popmax 0.149%, mid); Associated with Inborn genetic diseases.

What condition is associated with LRP12 p.Ala554Ser (c.1660G>T)?

LRP12 p.Ala554Ser (c.1660G>T) is associated with Inborn genetic diseases (ClinVar).

How common is LRP12 p.Ala554Ser (c.1660G>T) in the general population?

LRP12 p.Ala554Ser (c.1660G>T) is rare (popmax 0.149%, mid) (gnomAD).

What do computational predictors say about LRP12 p.Ala554Ser (c.1660G>T)?

AlphaMissense predicts likely benign (score 0.2614) — an in-silico prediction, not a clinical call.

LRP12 p.Ala554Ser

c.1660G>T · VCV3868137

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2614 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2614	likely benign
REVEL	0.639	indeterminate
SaProt	LLR -5.49	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 18 kb · p 1.2e-07 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 0.149% Middle Eastern · 9/6,060 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.00397% 64/1,613,824 alleles · rare exomes 55/1,461,492 · genomes 9/152,332 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.149%	673
Remaining individualsnot grpmax-eligible	0.0224%	4,463
African / African-American	0.00533%	18,763
European (non-Finnish)	0.00305%	32,772
Admixed American	0.00167%	60,026

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: LRP12
Protein: p.Ala554Ser
Coding: c.1660G>T
MANE Select: NM_013437
Type: single nucleotide variant
Location: chr8:104495130 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.10

Full LRP12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LRP12 p.Arg732Cys Uncertain significance ★★ ⚠ same condition
LRP12 p.Ala204Gly Uncertain significance ★ ⚠ same condition
LRP12 p.Ala2Val Uncertain significance ★ ⚠ same condition
LRP12 p.Ala684Val Uncertain significance ★ ⚠ same condition
LRP12 p.Ala82Thr Uncertain significance ★ ⚠ same condition
LRP12 p.Arg102Ser Uncertain significance ★ ⚠ same condition
LRP12 p.Arg172Cys Uncertain significance ★ ⚠ same condition
LRP12 p.Arg172His Uncertain significance ★ ⚠ 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/lrp12-p-ala554ser (accessed [today's date]).

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