Is HAL p.Arg584Cys (c.1750C>T) pathogenic?

HAL p.Arg584Cys (c.1750C>T) is classified Uncertain significance in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: likely pathogenic (0.7225); Ultra-rare (popmax 0.033%, mid).

How common is HAL p.Arg584Cys (c.1750C>T) in the general population?

HAL p.Arg584Cys (c.1750C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about HAL p.Arg584Cys (c.1750C>T)?

AlphaMissense predicts likely pathogenic (score 0.7225) — an in-silico prediction, not a clinical call.

HAL p.Arg584Cys

c.1750C>T · VCV3283434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7225 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7225	likely pathogenic
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -13.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.45 · evaluated, not missing
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 0.033% Middle Eastern · 2/6,066 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.0109% 175/1,604,886 alleles · ultra-rare exomes 169/1,452,708 · genomes 6/152,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,033
European (non-Finnish)	0.0133%	7,511
South Asian	0.011%	9,091
Remaining individualsnot grpmax-eligible	0.00644%	15,539
African / African-American	0.00268%	37,375
East Asian	0.00223%	44,844

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.Arg584Cys
Coding: c.1750C>T
MANE Select: NM_002108
Type: single nucleotide variant
Location: chr12:95976611 (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-arg584cys (accessed [today's date]).

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