Is LBHD1 p.Ser72Arg (c.216T>G) pathogenic?

LBHD1 p.Ser72Arg (c.216T>G) is classified Uncertain significance in LBHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: ambiguous (0.4392); Ultra-rare (popmax 0.0222%, nfe).

How common is LBHD1 p.Ser72Arg (c.216T>G) in the general population?

LBHD1 p.Ser72Arg (c.216T>G) is ultra-rare (popmax 0.0222%, nfe) (gnomAD).

What do computational predictors say about LBHD1 p.Ser72Arg (c.216T>G)?

AlphaMissense predicts ambiguous (score 0.4392) — an in-silico prediction, not a clinical call.

LBHD1 p.Ser72Arg

c.216T>G · rs138957379 · VCV3117984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4392 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4392	ambiguous
REVEL	0.033	moderately benign-leaning
SaProt	LLR -7.63	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.11	GERP -5.2
Regional constraint	o/e 1.08	unconstrained · MANE · 6,899 bp · p 0.13 · regional, not allelic
Overall
CADD	19.1	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 S98R vs ClinVar S72R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0222% European (non-Finnish) · 262/1,180,008 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0191%

Overall 0.0167% 270/1,613,846 alleles · ultra-rare exomes 256/1,461,892 · genomes 14/151,954 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0222%	4,504
African / African-American	0.00668%	14,969
Remaining individualsnot grpmax-eligible	0.0048%	20,828

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.Ser72Arg
Coding: c.216T>G
MANE Select: NM_024099
dbSNP: rs138957379
Type: single nucleotide variant
Location: chr11:62669738 (GRCh38)
Gene constraint: LOEUF 1.281 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.51
Residue 98 UniProt numbering: the lbh domain

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

Similar variants

UQCC3 p.Glu72Val Uncertain significance ★ ⚠ same residue
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

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-ser72arg (accessed [today's date]).

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