Is HAO2 p.Val338Phe (c.1012G>T) pathogenic?

HAO2 p.Val338Phe (c.1012G>T) is classified Uncertain significance in HAO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely benign (0.2841); Ultra-rare (popmax 0.0648%, sas).

How common is HAO2 p.Val338Phe (c.1012G>T) in the general population?

HAO2 p.Val338Phe (c.1012G>T) is ultra-rare (popmax 0.0648%, sas) (gnomAD).

What do computational predictors say about HAO2 p.Val338Phe (c.1012G>T)?

AlphaMissense predicts likely benign (score 0.2841) — an in-silico prediction, not a clinical call.

HAO2 p.Val338Phe

c.1012G>T · rs143670501 · VCV2214728

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0648%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2841	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -10.65	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.45, phastCons 0.56
Regional constraint	o/e 1.11	unconstrained · MANE · 13 kb · p 0.027 · regional, not allelic
Overall
CADD	18.78	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 0.0648% South Asian · 59/91,050 alleles

Filtering AF 0.0515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0467%

Overall 0.0167% 269/1,613,176 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.768%	130
South Asiangrpmax	0.0648%	1,543
Finnishnot grpmax-eligible	0.0328%	3,048
European (non-Finnish)	0.014%	7,148
Remaining individualsnot grpmax-eligible	0.0128%	7,805
Admixed American	0.01%	9,994
African / African-American	0.004%	24,982

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val338Phe
Coding: c.1012G>T
MANE Select: NM_016527
dbSNP: rs143670501
Type: single nucleotide variant
Location: chr1:119393796 (GRCh38)
Gene constraint: LOEUF 1.33 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.99
Residue 338: 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-val338phe (accessed [today's date]).

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