Is SARS2 p.Arg431His (c.1292G>A) pathogenic?

SARS2 p.Arg431His (c.1292G>A) is classified Conflicting classifications of pathogenicity in SARS2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.2021); Very rare (popmax 0.00314%, nfe); Associated with hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome.

What condition is associated with SARS2 p.Arg431His (c.1292G>A)?

SARS2 p.Arg431His (c.1292G>A) is associated with hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome (ClinVar).

How common is SARS2 p.Arg431His (c.1292G>A) in the general population?

SARS2 p.Arg431His (c.1292G>A) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about SARS2 p.Arg431His (c.1292G>A)?

AlphaMissense predicts likely benign (score 0.2021) — an in-silico prediction, not a clinical call.

SARS2 p.Arg431His

Q: How is Hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1292G>A · rs146193366 · VCV894086

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2021 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome

Computational evidence

Protein change
AlphaMissense	0.2021	likely benign
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -13.35	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.68, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 15 kb · p 0.21 · regional, not allelic
Overall
CADD	33.0	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 0.00314% European (non-Finnish) · 37/1,179,944 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.0114% 184/1,613,890 alleles · very rare exomes 169/1,461,604 · genomes 15/152,286 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.405%	247
Remaining individualsnot grpmax-eligible	0.04%	2,500
European (non-Finnish)grpmax	0.00314%	31,890
South Asian	0.0022%	45,537

Ashkenazi Jewish 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: SARS2
Protein: p.Arg431His
Coding: c.1292G>A
MANE Select: NM_017827
dbSNP: rs146193366
Type: single nucleotide variant
Location: chr19:38916092 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.58 · 6 PDB
Residue 431: an α-helix

Full SARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SARS2 p.Arg431Cys Uncertain significance ★★ ⚠ same residue
SARS2 c.759+4T>C Uncertain significance ★★ same condition
SARS2 c.-5C>A Uncertain significance ★★ same condition
SARS2 p.Ala167Val Uncertain significance ★★ ⚠ same condition
SARS2 p.Ala463Val Uncertain significance ★★ ⚠ same condition
SARS2 p.Ala516Ser Uncertain significance ★★ ⚠ same condition
SARS2 p.Ala73Pro Uncertain significance ★★ ⚠ same condition
SARS2 p.Arg118Gln Uncertain significance ★★ ⚠ same condition

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/sars2-p-arg431his (accessed [today's date]).

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