Is SI p.Arg52His (c.155G>A) pathogenic?

SI p.Arg52His (c.155G>A) is classified Conflicting classifications of pathogenicity in SI (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-19). AlphaMissense: likely benign (0.0898); Ultra-rare (popmax 0.0484%, sas); Associated with Inborn genetic diseases.

What condition is associated with SI p.Arg52His (c.155G>A)?

SI p.Arg52His (c.155G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SI p.Arg52His (c.155G>A) in the general population?

SI p.Arg52His (c.155G>A) is ultra-rare (popmax 0.0484%, sas) (gnomAD).

What do computational predictors say about SI p.Arg52His (c.155G>A)?

AlphaMissense predicts likely benign (score 0.0898) — an in-silico prediction, not a clinical call.

SI p.Arg52His

c.155G>A · rs777987599 · VCV2383198

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0484%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0898	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -7.63	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 -0.17	GERP -0.35
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	2.7	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 0.0484% South Asian · 44/90,966 alleles

Filtering AF 0.037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00366% 59/1,610,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0484%	2,067
East Asian	0.00224%	44,636
Finnishnot grpmax-eligible	0.00156%	63,918
European (non-Finnish)	0.0011%	90,576

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: SI
Protein: p.Arg52His
Coding: c.155G>A
MANE Select: NM_001041
dbSNP: rs777987599
Type: single nucleotide variant
Location: chr3:165074631 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.86 · 2 PDB
Residue 52: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SI p.Arg52Cys Uncertain significance ★★ ⚠ same residue
SI p.Ala1654Asp Uncertain significance ★★ ⚠ same condition
SI p.Ala429Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala573Val Uncertain significance ★★ ⚠ same condition
SI p.Ala760Val Uncertain significance ★★ ⚠ same condition
SI p.Ala808Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala826Asp Uncertain significance ★★ ⚠ same condition
SI p.Arg1078Gln 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/si-p-arg52his (accessed [today's date]).

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