Is HAO2 p.Arg22Trp (c.64C>T) pathogenic?

HAO2 p.Arg22Trp (c.64C>T) is classified Likely benign in HAO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely benign (0.0604); Ultra-rare (popmax 0.0143%, sas).

How common is HAO2 p.Arg22Trp (c.64C>T) in the general population?

HAO2 p.Arg22Trp (c.64C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about HAO2 p.Arg22Trp (c.64C>T)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

HAO2 p.Arg22Trp

c.64C>T · VCV4033632

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -1.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP -0.57, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 13 kb · p 0.027 · regional, not allelic
Overall
CADD	12.61	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 0.0143% South Asian · 13/91,000 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00662%

Overall 0.0018% 29/1,609,548 alleles · ultra-rare exomes 27/1,457,448 · genomes 2/152,100 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,000
Admixed American	0.00667%	14,993
European (non-Finnish)	0.00102%	97,993

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.Arg22Trp
Coding: c.64C>T
MANE Select: NM_016527
Type: single nucleotide variant
Location: chr1:119381149 (GRCh38)
Gene constraint: LOEUF 1.33 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.99
Residue 22: the fmn hydroxy acid dehydrogenase domain

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

Similar variants

HAO2 p.Arg22Gln Uncertain significance ★ ⚠ same residue
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.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-arg22trp (accessed [today's date]).

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