Is HLCS p.Pro194Ser (c.580C>T) pathogenic?

HLCS p.Pro194Ser (c.580C>T) is classified Likely benign in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely benign (0.0744); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with HLCS p.Pro194Ser (c.580C>T)?

HLCS p.Pro194Ser (c.580C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HLCS p.Pro194Ser (c.580C>T) in the general population?

HLCS p.Pro194Ser (c.580C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about HLCS p.Pro194Ser (c.580C>T)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

HLCS p.Pro194Ser

c.580C>T · VCV3858047

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -6.71	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 -0.47	GERP -3.8
Regional constraint	o/e 0.90	unconstrained · MANE · 212 kb · p 0.00098 · regional, not allelic
Overall
CADD	0.024	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 P47S vs ClinVar P194S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,916 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00031% 5/1,614,008 alleles · very rare exomes 4/1,461,828 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,458
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.47e-05%	1,180,020

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: HLCS
Protein: p.Pro194Ser
Coding: c.580C>T
MANE Select: NM_001352514
Type: single nucleotide variant
Location: chr21:36937306 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.33
Residue 47 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.Pro194Leu Uncertain significance ★★ ⚠ same residue
HLCS p.Pro194= Likely benign ★ same residue
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

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-pro194ser (accessed [today's date]).

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