Is S100B p.His91Arg (c.272A>G) pathogenic?

S100B p.His91Arg (c.272A>G) is classified Uncertain significance in S100B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.0664); Ultra-rare (popmax 0.0117%, amr).

How common is S100B p.His91Arg (c.272A>G) in the general population?

S100B p.His91Arg (c.272A>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about S100B p.His91Arg (c.272A>G)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

S100B p.His91Arg

c.272A>G · rs758094032 · VCV2398383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.99	donor gain · deltas
Pangolin	Δ0.87	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2	GERP 0.52, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,049 bp · p 0.23 · regional, not allelic
Overall
CADD	18.26	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 0.0117% Admixed American · 7/59,946 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000434% 7/1,613,838 alleles · ultra-rare exomes 7/1,461,500 · genomes 0/152,338 · joint denominator

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: S100B
Protein: p.His91Arg
Coding: c.272A>G
MANE Select: NM_006272
dbSNP: rs758094032
Type: single nucleotide variant
Location: chr21:46599370 (GRCh38)
Gene constraint: LOEUF 1.494 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 91.08 · 15 PDB
Residue 91: a binding site

Full S100B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

S100B p.Asp13Asn Uncertain significance ★ ⚠ same type
S100B p.Ile12Thr Uncertain significance ★ ⚠ same type
S100B p.Leu36Phe Uncertain significance ★ ⚠ same type
S100B p.Leu45Ser Uncertain significance ★ ⚠ same type
S100B p.Leu4Pro Uncertain significance ★ ⚠ same type
S100B p.Phe74Tyr Uncertain significance ★ ⚠ same type
S100B p.Ser19Pro Uncertain significance ★ ⚠ same type
S100B p.Val53Leu 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/s100b-p-his91arg (accessed [today's date]).

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