Is TYROBP p.Arg80Trp (c.238C>T) pathogenic?

TYROBP p.Arg80Trp (c.238C>T) is classified Conflicting classifications of pathogenicity in TYROBP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.2628); Rare (popmax 0.383%, afr).

How common is TYROBP p.Arg80Trp (c.238C>T) in the general population?

TYROBP p.Arg80Trp (c.238C>T) is rare (popmax 0.383%, afr) (gnomAD).

What do computational predictors say about TYROBP p.Arg80Trp (c.238C>T)?

AlphaMissense predicts likely benign (score 0.2628) — an in-silico prediction, not a clinical call.

TYROBP p.Arg80Trp

c.238C>T · rs140188939 · VCV501065

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2628 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.383%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2628	likely benign
REVEL	0.593	indeterminate
SaProt	LLR -8.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP -1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 3,656 bp · p 0.43 · regional, not allelic
Overall
CADD	22.1	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 0.383% African / African-American · 287/75,000 alleles

Filtering AF 0.346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.332%

Overall 0.0231% 372/1,609,566 alleles · rare exomes 204/1,457,344 · genomes 168/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.383%	261
Admixed American	0.0936%	1,069
Remaining individualsnot grpmax-eligible	0.0353%	2,835
South Asian	0.00221%	45,180
European (non-Finnish)	0.000509%	196,370

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: TYROBP
Protein: p.Arg80Trp
Coding: c.238C>T
MANE Select: NM_003332
dbSNP: rs140188939
Type: single nucleotide variant
Location: chr19:35907256 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.10 · 5 PDB
Residue 80: a UniProt-annotated variant site (found in patients with early-onset alzheimer disease; uncertain significance); the itam domain; the 'disordered' region

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

Similar variants

TYROBP p.Ala44Thr Uncertain significance ★★ ⚠ same type
TYROBP p.Arg70Trp Uncertain significance ★★ ⚠ same type
TYROBP p.Asp104Asn Uncertain significance ★★ ⚠ same type
TYROBP p.Asp32Asn Uncertain significance ★★ ⚠ same type
TYROBP p.Pro40Leu Uncertain significance ★★ same type
TYROBP p.Ser99Leu Uncertain significance ★★ ⚠ same type
TYROBP p.Val38Met Uncertain significance ★★ ⚠ same type
TYROBP p.Val42Met 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/tyrobp-p-arg80trp (accessed [today's date]).

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