Is HAO2 p.Arg50Trp (c.148C>T) pathogenic?

HAO2 p.Arg50Trp (c.148C>T) is classified Uncertain significance in HAO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: likely benign (0.2655); Ultra-rare (popmax 0.06%, amr).

How common is HAO2 p.Arg50Trp (c.148C>T) in the general population?

HAO2 p.Arg50Trp (c.148C>T) is ultra-rare (popmax 0.06%, amr) (gnomAD).

What do computational predictors say about HAO2 p.Arg50Trp (c.148C>T)?

AlphaMissense predicts likely benign (score 0.2655) — an in-silico prediction, not a clinical call.

HAO2 p.Arg50Trp

c.148C>T · rs199705214 · VCV3104184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2655 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2655	likely benign
REVEL	0.471	indeterminate
SaProt	LLR -14.26	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.78	GERP 0.56, phastCons 0.2
Regional constraint	o/e 1.11	unconstrained · MANE · 13 kb · p 0.027 · regional, not allelic
Overall
CADD	23.6	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 0.06% Admixed American · 36/60,004 alleles

Filtering AF 0.0445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0392%

Overall 0.0133% 214/1,613,610 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.06%	1,667
South Asian	0.0187%	5,354
East Asian	0.0178%	5,602
Remaining individualsnot grpmax-eligible	0.0176%	5,680
European (non-Finnish)	0.0115%	8,674
African / African-American	0.008%	12,508

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: HAO2
Protein: p.Arg50Trp
Coding: c.148C>T
MANE Select: NM_016527
dbSNP: rs199705214
Type: single nucleotide variant
Location: chr1:119382931 (GRCh38)
Gene constraint: LOEUF 1.33 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.99
Residue 50: the fmn hydroxy acid dehydrogenase domain

Full HAO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HAO2 p.Ala11Val Uncertain significance ★ ⚠ same type
HAO2 p.Ala120Val Uncertain significance ★ ⚠ same type
HAO2 p.Ala289Thr Uncertain significance ★ ⚠ same type
HAO2 p.Ala93Gly Uncertain significance ★ ⚠ same type
HAO2 p.Ala98Glu Uncertain significance ★ ⚠ same type
HAO2 p.Arg22Gln Uncertain significance ★ ⚠ same type
HAO2 p.Arg281Gln Uncertain significance ★ ⚠ same type
HAO2 p.Arg301Lys 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/hao2-p-arg50trp (accessed [today's date]).

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