Is LRRC59 p.Pro233Ser (c.697C>T) pathogenic?

LRRC59 p.Pro233Ser (c.697C>T) is classified Uncertain significance in LRRC59 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14). AlphaMissense: likely benign (0.0805); Ultra-rare (popmax 0.0754%, eas).

How common is LRRC59 p.Pro233Ser (c.697C>T) in the general population?

LRRC59 p.Pro233Ser (c.697C>T) is ultra-rare (popmax 0.0754%, eas) (gnomAD).

What do computational predictors say about LRRC59 p.Pro233Ser (c.697C>T)?

AlphaMissense predicts likely benign (score 0.0805) — an in-silico prediction, not a clinical call.

LRRC59 p.Pro233Ser

c.697C>T · rs543176399 · VCV2492067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0805 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0754%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0805	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP 0.85, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 0.0018 · regional, not allelic
Overall
CADD	18.43	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 0.0754% East Asian · 31/41,118 alleles

Filtering AF 0.0546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0475%

Overall 0.00232% 36/1,553,106 alleles · ultra-rare exomes 29/1,400,768 · genomes 7/152,338 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0754%	1,326
Remaining individualsnot grpmax-eligible	0.00166%	60,194
European (non-Finnish)	0.000348%	286,961

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: LRRC59
Protein: p.Pro233Ser
Coding: c.697C>T
MANE Select: NM_018509
dbSNP: rs543176399
Type: single nucleotide variant
Location: chr17:50383215 (GRCh38)
Gene constraint: LOEUF 0.782 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.90
Residue 233: the 'disordered' region

Full LRRC59 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LRRC59 p.Ala141Thr Uncertain significance ★ ⚠ same type
LRRC59 p.Ala260Val Uncertain significance ★ ⚠ same type
LRRC59 p.Ala287Val Uncertain significance ★ ⚠ same type
LRRC59 p.Arg12Pro Uncertain significance ★ ⚠ same type
LRRC59 p.Arg157Trp Uncertain significance ★ ⚠ same type
LRRC59 p.Arg161Trp Uncertain significance ★ ⚠ same type
LRRC59 p.Arg162Gln Uncertain significance ★ ⚠ same type
LRRC59 p.Arg162Trp Uncertain significance ★ ⚠ 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/lrrc59-p-pro233ser (accessed [today's date]).

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