Is HLCS p.Ala233Pro (c.697G>C) pathogenic?

HLCS p.Ala233Pro (c.697G>C) is classified Uncertain significance in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.0905); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with HLCS p.Ala233Pro (c.697G>C)?

HLCS p.Ala233Pro (c.697G>C) is associated with Inborn genetic diseases (ClinVar).

How common is HLCS p.Ala233Pro (c.697G>C) in the general population?

HLCS p.Ala233Pro (c.697G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HLCS p.Ala233Pro (c.697G>C)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

HLCS p.Ala233Pro

c.697G>C · VCV3858045

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.31	GERP -1.3
Regional constraint	o/e 0.90	unconstrained · MANE · 212 kb · p 0.00098 · regional, not allelic
Overall
CADD	11.72	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A86P vs ClinVar A233P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HLCS
Protein: p.Ala233Pro
Coding: c.697G>C
MANE Select: NM_001352514
Type: single nucleotide variant
Location: chr21:36937189 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.33
Residue 86 UniProt numbering: the 'disordered' region

Full HLCS 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

HLCS p.Arg330Trp Uncertain significance ★★ ⚠ same condition
HLCS p.Arg627Cys Uncertain significance ★★ ⚠ same condition
HLCS p.Asn303Ile Uncertain significance ★★ ⚠ same condition
HLCS p.Asp318Asn Uncertain significance ★★ ⚠ same condition
HLCS p.Gln161Glu Uncertain significance ★★ ⚠ same condition
HLCS p.Gln386His Uncertain significance ★★ ⚠ same condition
HLCS p.Glu739Lys Uncertain significance ★★ ⚠ same condition
HLCS p.Glu850Lys 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/hlcs-p-ala233pro (accessed [today's date]).

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