Is LIPH p.Pro421Leu (c.1262C>T) pathogenic?

LIPH p.Pro421Leu (c.1262C>T) is classified Uncertain significance in LIPH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-09). AlphaMissense: likely benign (0.1074); Ultra-rare (popmax 0.0213%, afr); Associated with Inborn genetic diseases.

What condition is associated with LIPH p.Pro421Leu (c.1262C>T)?

LIPH p.Pro421Leu (c.1262C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LIPH p.Pro421Leu (c.1262C>T) in the general population?

LIPH p.Pro421Leu (c.1262C>T) is ultra-rare (popmax 0.0213%, afr) (gnomAD).

What do computational predictors say about LIPH p.Pro421Leu (c.1262C>T)?

AlphaMissense predicts likely benign (score 0.1074) — an in-silico prediction, not a clinical call.

LIPH p.Pro421Leu

c.1262C>T · rs373209531 · VCV2510895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1074 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1074	likely benign
REVEL	0.556	indeterminate
SaProt	LLR -10.09	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 10	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 44 kb · p 0.056 · 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 0.0213% African / African-American · 16/75,006 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00186% 30/1,614,066 alleles · ultra-rare exomes 15/1,461,858 · genomes 15/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0213%	4,688
Remaining individualsnot grpmax-eligible	0.0032%	31,250
South Asian	0.0022%	45,542
Admixed American	0.00167%	60,014
European (non-Finnish)	0.000763%	131,111

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: LIPH
Protein: p.Pro421Leu
Coding: c.1262C>T
MANE Select: NM_139248
dbSNP: rs373209531
Type: single nucleotide variant
Location: chr3:185511530 (GRCh38)
Gene constraint: LOEUF 0.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.89
Residue 421: a UniProt-annotated variant site (in arwh2)

Full LIPH 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

LIPH p.Ala180Gly Uncertain significance ★★ ⚠ same condition
LIPH p.Arg110Leu Uncertain significance ★★ ⚠ same condition
LIPH p.Ile336Met Uncertain significance ★★ ⚠ same condition
LIPH p.Ala180Thr Uncertain significance ★ ⚠ same condition
LIPH p.Ala198Val Uncertain significance ★ ⚠ same condition
LIPH p.Ala267Glu Uncertain significance ★ ⚠ same condition
LIPH p.Ala54Thr Uncertain significance ★ ⚠ same condition
LIPH p.Arg110Gln 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/liph-p-pro421leu (accessed [today's date]).

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