Is S100B p.Phe74Tyr (c.221T>A) pathogenic?

S100B p.Phe74Tyr (c.221T>A) is classified Uncertain significance in S100B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely benign (0.1573); Absent from gnomAD v4.1.

How common is S100B p.Phe74Tyr (c.221T>A) in the general population?

S100B p.Phe74Tyr (c.221T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about S100B p.Phe74Tyr (c.221T>A)?

AlphaMissense predicts likely benign (score 0.1573) — an in-silico prediction, not a clinical call.

S100B p.Phe74Tyr

c.221T>A · VCV4580507

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1573 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1573	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -6.01	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 6.6	GERP -1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,049 bp · p 0.23 · regional, not allelic
Overall
CADD	21.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: S100B
Protein: p.Phe74Tyr
Coding: c.221T>A
MANE Select: NM_006272
Type: single nucleotide variant
Location: chr21:46599421 (GRCh38)
Gene constraint: LOEUF 1.494 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 91.08 · 15 PDB
Residue 74: an α-helix; the ef-hand 2 domain

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.His91Arg 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.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-phe74tyr (accessed [today's date]).

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