Is SI p.Arg435His (c.1304G>A) pathogenic?

SI p.Arg435His (c.1304G>A) is classified Uncertain significance in SI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-15). AlphaMissense: likely benign (0.1419); Ultra-rare (popmax 0.0151%, amr).

How common is SI p.Arg435His (c.1304G>A) in the general population?

SI p.Arg435His (c.1304G>A) is ultra-rare (popmax 0.0151%, amr) (gnomAD).

What do computational predictors say about SI p.Arg435His (c.1304G>A)?

AlphaMissense predicts likely benign (score 0.1419) — an in-silico prediction, not a clinical call.

SI p.Arg435His

c.1304G>A · rs536628141 · VCV1898767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1419 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0151%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1419	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -4.21	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 -1	GERP -0.76
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	14.12	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 0.0151% Admixed American · 9/59,718 alleles

Filtering AF 0.00777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00581%

Overall 0.00105% 17/1,612,358 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0151%	6,635
Remaining individualsnot grpmax-eligible	0.00481%	20,802
African / African-American	0.004%	24,975
East Asian	0.00224%	44,700
European (non-Finnish)	8.48e-05%	1,179,126

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.Arg435His
Coding: c.1304G>A
MANE Select: NM_001041
dbSNP: rs536628141
Type: single nucleotide variant
Location: chr3:165059057 (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 435: the 'isomaltase' region

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

Similar variants

SI p.Arg435Cys Uncertain significance ★★ ⚠ same residue
SI p.Arg435= Likely benign ★ same residue
SI c.2426+1G>A Likely pathogenic ★★ same type
SI c.2737-2A>G Likely pathogenic ★★ same type
SI c.2893-1G>A Likely pathogenic ★★ same type
SI c.3099+1G>C Likely pathogenic ★★ same type
SI c.3521-1G>T Likely pathogenic ★★ same type
SI c.373+1G>A Likely pathogenic ★★ 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/si-p-arg435his (accessed [today's date]).

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