Is HELZ p.Pro599Ser (c.1795C>T) pathogenic?

HELZ p.Pro599Ser (c.1795C>T) is classified Uncertain significance in HELZ (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: ambiguous (0.5402); Ultra-rare (popmax 0.027%, nfe).

How common is HELZ p.Pro599Ser (c.1795C>T) in the general population?

HELZ p.Pro599Ser (c.1795C>T) is ultra-rare (popmax 0.027%, nfe) (gnomAD).

What do computational predictors say about HELZ p.Pro599Ser (c.1795C>T)?

AlphaMissense predicts ambiguous (score 0.5402) — an in-silico prediction, not a clinical call.

HELZ p.Pro599Ser

c.1795C>T · VCV3283964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5402 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.027%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5402	ambiguous
REVEL	0.761	pathogenic-leaning
SaProt	LLR -5.51	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 70 kb · p 8.8e-23 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.027% European (non-Finnish) · 319/1,179,354 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0236%

Overall 0.0214% 345/1,613,142 alleles · ultra-rare exomes 326/1,461,026 · genomes 19/152,116 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0272%	3,674
European (non-Finnish)grpmax	0.027%	3,697
African / African-American	0.00534%	18,720
Finnishnot grpmax-eligible	0.00312%	32,010
East Asian	0.00223%	44,814
Admixed American	0.00167%	59,974
South Asian	0.0011%	91,060

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: HELZ
Protein: p.Pro599Ser
Coding: c.1795C>T
MANE Select: NM_014877
Type: single nucleotide variant
Location: chr17:67166578 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.24

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

Similar variants

HELZ p.Arg1652His Uncertain significance ★★ ⚠ same type
HELZ p.Ile1108Val Likely pathogenic ★ ⚠ same type
HELZ c.*4461C>T Uncertain significance ★ same type
HELZ p.Ala1161Pro Uncertain significance ★ same type
HELZ p.Ala1351Thr Uncertain significance ★ ⚠ same type
HELZ p.Ala1430Asp Uncertain significance ★ same type
HELZ p.Ala1437Val Uncertain significance ★ ⚠ same type
HELZ p.Ala1467Thr 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/helz-p-pro599ser (accessed [today's date]).

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