Is HAO1 p.Pro215Ser (c.643C>T) pathogenic?

HAO1 p.Pro215Ser (c.643C>T) is classified Uncertain significance in HAO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.1811); Ultra-rare (popmax 0.035%, amr).

How common is HAO1 p.Pro215Ser (c.643C>T) in the general population?

HAO1 p.Pro215Ser (c.643C>T) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about HAO1 p.Pro215Ser (c.643C>T)?

AlphaMissense predicts likely benign (score 0.1811) — an in-silico prediction, not a clinical call.

HAO1 p.Pro215Ser

c.643C>T · VCV4674871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1811 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1811	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -5.72	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 5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 57 kb · p 0.5 · regional, not allelic
Overall
CADD	20.8	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 0.035% Admixed American · 21/59,996 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00149% 24/1,611,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,857
Remaining individualsnot grpmax-eligible	0.0016%	62,336
African / African-American	0.00134%	74,834
European (non-Finnish)	8.49e-05%	1,177,426

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: HAO1
Protein: p.Pro215Ser
Coding: c.643C>T
MANE Select: NM_017545
Type: single nucleotide variant
Location: chr20:7906232 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.55 · 21 PDB
Residue 215: the fmn hydroxy acid dehydrogenase domain

Full HAO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HAO1 p.Gly165Cys Pathogenic ★ same type
HAO1 p.Ala210Ser Uncertain significance ★ ⚠ same type
HAO1 p.Ala244Thr Uncertain significance ★ same type
HAO1 p.Ala345Val Uncertain significance ★ ⚠ same type
HAO1 p.Ala366Pro Uncertain significance ★ ⚠ same type
HAO1 p.Ala81Thr Uncertain significance ★ ⚠ same type
HAO1 p.Arg127Cys Uncertain significance ★ ⚠ same type
HAO1 p.Arg137Gln 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/hao1-p-pro215ser (accessed [today's date]).

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