Is TYR p.Pro296Ser (c.886C>T) pathogenic?

TYR p.Pro296Ser (c.886C>T) is classified Uncertain significance in TYR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-24). AlphaMissense: likely benign (0.1721); Ultra-rare (popmax 0.0791%, sas); Associated with Inborn genetic diseases.

What condition is associated with TYR p.Pro296Ser (c.886C>T)?

TYR p.Pro296Ser (c.886C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TYR p.Pro296Ser (c.886C>T) in the general population?

TYR p.Pro296Ser (c.886C>T) is ultra-rare (popmax 0.0791%, sas) (gnomAD).

What do computational predictors say about TYR p.Pro296Ser (c.886C>T)?

AlphaMissense predicts likely benign (score 0.1721) — an in-silico prediction, not a clinical call.

TYR p.Pro296Ser

c.886C>T · rs752062836 · VCV1943867

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0791%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1721	likely benign
REVEL	0.776	moderately pathogenic-leaning
SaProt	LLR -8.19	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 117 kb · p 0.00089 · regional, not allelic
Overall
CADD	23.8	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 0.0791% South Asian · 72/91,076 alleles

Filtering AF 0.0643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.059%

Overall 0.00471% 76/1,613,588 alleles · ultra-rare exomes 74/1,461,468 · genomes 2/152,120 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0791%	1,265
Middle Eastern	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.0048%	20,825

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: TYR
Protein: p.Pro296Ser
Coding: c.886C>T
MANE Select: NM_000372
dbSNP: rs752062836
Type: single nucleotide variant
Location: chr11:89191268 (GRCh38)
Gene constraint: LOEUF 1.346 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79 · 1 PDB
Residue 296: the 'disordered' region

Full TYR 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

TYR p.Pro296Leu Uncertain significance ★ ⚠ same residue
TYR p.Pro296= Likely benign ★ same residue
TYR p.Arg298Gln Uncertain significance ★★ ⚠ same condition
TYR p.Arg405Cys Uncertain significance ★★ ⚠ same condition
TYR p.Asn230Lys Uncertain significance ★★ ⚠ same condition
TYR p.Asp169Asn Uncertain significance ★★ ⚠ same condition
TYR p.Glu281Gly Uncertain significance ★★ ⚠ same condition
TYR p.Leu140Ser 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/tyr-p-pro296ser (accessed [today's date]).

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