Is HMBS p.Arg164Ser (c.492G>T) pathogenic?

HMBS p.Arg164Ser (c.492G>T) is classified Uncertain significance in HMBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-26). AlphaMissense: ambiguous (0.3817); Very rare (popmax 0.00687%, nfe).

How common is HMBS p.Arg164Ser (c.492G>T) in the general population?

HMBS p.Arg164Ser (c.492G>T) is very rare (popmax 0.00687%, nfe) (gnomAD).

What do computational predictors say about HMBS p.Arg164Ser (c.492G>T)?

AlphaMissense predicts ambiguous (score 0.3817) — an in-silico prediction, not a clinical call.

HMBS p.Arg164Ser

c.492G>T · rs752504488 · VCV1426824

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00687%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3817	ambiguous
REVEL	0.53	indeterminate
SaProt	LLR -8.36	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.14, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,246 bp · p 0.0046 · regional, not allelic
Overall
CADD	24.2	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 0.00687% European (non-Finnish) · 81/1,178,714 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00509% 82/1,612,566 alleles · very rare exomes 78/1,460,350 · genomes 4/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00687%	14,552
African / African-American	0.00134%	74,902

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: HMBS
Protein: p.Arg164Ser
Coding: c.492G>T
MANE Select: NM_000190
dbSNP: rs752504488
Type: single nucleotide variant
Location: chr11:119090259 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 164: a β-strand

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

Similar variants

HMBS p.Arg164Gly Uncertain significance ★ ⚠ same residue
HMBS p.Arg164= Likely benign ★ same residue
HMBS p.Arg164delinsSerTer Pathogenic ★ same residue
HMBS p.Arg164del Uncertain significance ★ same residue
HMBS c.160+5G>C Pathogenic/Likely pathogenic ★★ same type
HMBS c.345-1G>A Pathogenic ★★ same type
HMBS c.613-1G>A Pathogenic ★★ same type
HMBS c.826-2A>T Pathogenic/Likely pathogenic ★★ 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/hmbs-p-arg164ser (accessed [today's date]).

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