Is HAL p.Arg390Cys (c.1168C>T) pathogenic?

HAL p.Arg390Cys (c.1168C>T) is classified Uncertain significance in HAL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely pathogenic (0.5905); Very rare (popmax 0.00688%, nfe).

How common is HAL p.Arg390Cys (c.1168C>T) in the general population?

HAL p.Arg390Cys (c.1168C>T) is very rare (popmax 0.00688%, nfe) (gnomAD).

What do computational predictors say about HAL p.Arg390Cys (c.1168C>T)?

AlphaMissense predicts likely pathogenic (score 0.5905) — an in-silico prediction, not a clinical call.

HAL p.Arg390Cys

c.1168C>T · rs367677601 · VCV2241762

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00688%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5905	likely pathogenic
REVEL	0.602	indeterminate
SaProt	LLR -11.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.18 · regional, not allelic
Overall
CADD	26.5	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 0.00688% European (non-Finnish) · 81/1,178,056 alleles

Filtering AF 0.00564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00552% 89/1,611,066 alleles · very rare exomes 86/1,459,808 · genomes 3/151,258 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00688%	14,544
Remaining individualsnot grpmax-eligible	0.00641%	15,601
African / African-American	0.00269%	37,243
East Asian	0.00223%	44,850
South Asian	0.0011%	90,988

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.Arg390Cys
Coding: c.1168C>T
MANE Select: NM_002108
dbSNP: rs367677601
Type: single nucleotide variant
Location: chr12:95985946 (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 p.Arg390His Uncertain significance ★ ⚠ same residue
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

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-arg390cys (accessed [today's date]).

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