Is HAL p.Arg568Cys (c.1702C>T) pathogenic?

HAL p.Arg568Cys (c.1702C>T) is classified Uncertain significance in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-22). AlphaMissense: likely pathogenic (0.5713); Ultra-rare (popmax 0.034%, sas).

How common is HAL p.Arg568Cys (c.1702C>T) in the general population?

HAL p.Arg568Cys (c.1702C>T) is ultra-rare (popmax 0.034%, sas) (gnomAD).

What do computational predictors say about HAL p.Arg568Cys (c.1702C>T)?

AlphaMissense predicts likely pathogenic (score 0.5713) — an in-silico prediction, not a clinical call.

HAL p.Arg568Cys

c.1702C>T · rs765722855 · VCV2329259

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5713	likely pathogenic
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -13.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.034% South Asian · 31/91,064 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00242% 39/1,612,974 alleles · ultra-rare exomes 38/1,460,780 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.034%	2,938
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,454
European (non-Finnish)	0.000509%	196,507

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: HAL
Protein: p.Arg568Cys
Coding: c.1702C>T
MANE Select: NM_002108
dbSNP: rs765722855
Type: single nucleotide variant
Location: chr12:95976659 (GRCh38)
Gene constraint: LOEUF 1.213 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.83

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

Similar variants

HAL c.*392C>T Uncertain significance ★★ same type
HAL p.Arg9Cys Uncertain significance ★★ ⚠ same type
HAL p.Asn476Lys Uncertain significance ★★ ⚠ same type
HAL p.Glu472Lys Uncertain significance ★★ ⚠ same type
HAL p.Gly165Ser Uncertain significance ★★ ⚠ same type
HAL p.Ile458Thr Uncertain significance ★★ ⚠ same type
HAL p.Leu242Met Uncertain significance ★★ ⚠ same type
HAL p.Phe485Leu 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/hal-p-arg568cys (accessed [today's date]).

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