Is LBHD1 p.Pro59Leu (c.176C>T) pathogenic?

LBHD1 p.Pro59Leu (c.176C>T) is classified Likely benign in LBHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: likely benign (0.1541); Ultra-rare (popmax 0.04%, amr).

How common is LBHD1 p.Pro59Leu (c.176C>T) in the general population?

LBHD1 p.Pro59Leu (c.176C>T) is ultra-rare (popmax 0.04%, amr) (gnomAD).

What do computational predictors say about LBHD1 p.Pro59Leu (c.176C>T)?

AlphaMissense predicts likely benign (score 0.1541) — an in-silico prediction, not a clinical call.

LBHD1 p.Pro59Leu

c.176C>T · rs199556999 · VCV3117983

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1541 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1541	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.6	GERP -3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 6,899 bp · p 0.13 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P85L vs ClinVar P59L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% Admixed American · 24/60,020 alleles

Filtering AF 0.0275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00223% 36/1,614,176 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,501
Remaining individualsnot grpmax-eligible	0.008%	12,502
East Asian	0.00223%	44,878
South Asian	0.0022%	45,540
African / African-American	0.00133%	75,042
European (non-Finnish)	0.000254%	393,345

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: LBHD1
Protein: p.Pro59Leu
Coding: c.176C>T
MANE Select: NM_024099
dbSNP: rs199556999
Type: single nucleotide variant
Location: chr11:62669778 (GRCh38)
Gene constraint: LOEUF 1.281 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.51
Residue 59: the lbh domain

Full LBHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

UQCC3 p.Arg48Lys Uncertain significance ★★ ⚠ same type
UQCC3 p.Glu52Ala Uncertain significance ★★ ⚠ same type
UQCC3 c.121-11C>T Benign ★★ same type
UQCC3 c.-399G>T Benign ★★ same type
UQCC3 p.Gly86Ser Likely benign ★★ same type
UQCC3 p.Gly89Ser Benign ★★ same type
UQCC3 p.Thr69Ile Likely benign ★★ same type
UQCC3 p.Trp76Gly Benign/Likely benign ★★ same type

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/lbhd1-p-pro59leu (accessed [today's date]).

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