Is HCCS p.Pro44Arg (c.131C>G) pathogenic?

HCCS p.Pro44Arg (c.131C>G) is classified Uncertain significance in HCCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0663); Very rare (popmax 8.27e-05%); Associated with Inborn genetic diseases.

What condition is associated with HCCS p.Pro44Arg (c.131C>G)?

HCCS p.Pro44Arg (c.131C>G) is associated with Inborn genetic diseases (ClinVar).

How common is HCCS p.Pro44Arg (c.131C>G) in the general population?

HCCS p.Pro44Arg (c.131C>G) is very rare (popmax 8.27e-05%) (gnomAD).

What do computational predictors say about HCCS p.Pro44Arg (c.131C>G)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

HCCS p.Pro44Arg

c.131C>G · VCV4621351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.27e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -7.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -0.32
Regional constraint	o/e 1.20	unconstrained · MANE · 5,260 bp · p 0.075 · regional, not allelic
Overall
CADD	10.95	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 8.27e-05%

Overall 8.27e-05% 1/1,209,144 alleles · very rare exomes 1/1,095,610 · genomes 0/113,534 · joint denominator

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: HCCS
Protein: p.Pro44Arg
Coding: c.131C>G
MANE Select: NM_005333
Type: single nucleotide variant
Location: chrX:11114865 (GRCh38)
Structure: AlphaFold pLDDT 78.84

Full HCCS 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

HCCS p.Pro44Leu Uncertain significance ★ ⚠ same residue
HCCS p.Ala19Pro Uncertain significance ★★ ⚠ same condition
HCCS p.Ala60Thr Uncertain significance ★★ ⚠ same condition
HCCS p.Ala17Ser Likely benign ★★ same condition
HCCS p.Ala262Gly Benign/Likely benign ★★ ⚠ same condition
HCCS p.Ala72Val Benign/Likely benign ★★ same condition
HCCS p.Ile150Val Benign/Likely benign ★★ same condition
HCCS p.Val255Ile Benign/Likely benign ★★ 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/hccs-p-pro44arg (accessed [today's date]).

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