Is HAO2 p.Leu83Phe (c.247C>T) pathogenic?

HAO2 p.Leu83Phe (c.247C>T) is classified Uncertain significance in HAO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely benign (0.2081); Very rare (popmax 8.48e-05%, nfe).

How common is HAO2 p.Leu83Phe (c.247C>T) in the general population?

HAO2 p.Leu83Phe (c.247C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about HAO2 p.Leu83Phe (c.247C>T)?

AlphaMissense predicts likely benign (score 0.2081) — an in-silico prediction, not a clinical call.

HAO2 p.Leu83Phe

c.247C>T · rs748115172 · VCV3104185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2081	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.061	GERP -3.1
Regional constraint	o/e 1.11	unconstrained · MANE · 13 kb · p 0.027 · regional, not allelic
Overall
CADD	10.65	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.48e-05% European (non-Finnish) · 1/1,179,512 alleles

Overall 6.85e-05% 1/1,460,840 alleles · very rare

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.Leu83Phe
Coding: c.247C>T
MANE Select: NM_016527
dbSNP: rs748115172
Type: single nucleotide variant
Location: chr1:119383030 (GRCh38)
Gene constraint: LOEUF 1.33 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.99
Residue 83: 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-leu83phe (accessed [today's date]).

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