Is TYR p.Pro21Ser (c.61C>T) pathogenic?

TYR p.Pro21Ser (c.61C>T) is classified Pathogenic in TYR (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-02-02). AlphaMissense: likely pathogenic (0.7703); Very rare (popmax 0.00314%, nfe); Associated with SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN.

What condition is associated with TYR p.Pro21Ser (c.61C>T)?

TYR p.Pro21Ser (c.61C>T) is associated with SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN, oculocutaneous albinism type 1A, oculocutaneous albinism type 1B (ClinVar).

How common is TYR p.Pro21Ser (c.61C>T) in the general population?

TYR p.Pro21Ser (c.61C>T) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about TYR p.Pro21Ser (c.61C>T)?

AlphaMissense predicts likely pathogenic (score 0.7703) — an in-silico prediction, not a clinical call.

TYR p.Pro21Ser

c.61C>T · rs61753178 · VCV3793

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.7703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN

Computational evidence

Protein change
AlphaMissense	0.7703	likely pathogenic ✓ concordant with ClinVar
REVEL	0.943	strongly pathogenic-leaning
SaProt	LLR -4.73	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 117 kb · p 0.00089 · regional, not allelic
Overall
CADD	25.0	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 0.00314% European (non-Finnish) · 37/1,180,034 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00229% 37/1,614,054 alleles · very rare

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.Pro21Ser
Coding: c.61C>T
MANE Select: NM_000372
dbSNP: rs61753178
Type: single nucleotide variant
Location: chr11:89178014 (GRCh38)
Gene constraint: LOEUF 1.346 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79 · 1 PDB
Residue 21: a UniProt-annotated variant site (in oca1a)

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

Disease context

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: oculocutaneous albinism type 1A oculocutaneous albinism type 1B

Similar variants

TYR p.Pro21Arg Uncertain significance ★ ⚠ same residue
TYR p.Pro21Thr Uncertain significance ★ ⚠ same residue
TYR c.1036+1G>A Pathogenic/Likely pathogenic ★★ same condition
TYR c.1036+2T>G Pathogenic ★★ same condition
TYR c.1037-1G>A Pathogenic/Likely pathogenic ★★ same condition
TYR c.1037-2A>G Pathogenic/Likely pathogenic ★★ same condition
TYR c.1037-3C>G Pathogenic/Likely pathogenic ★★ same condition
TYR c.1037-7T>A Pathogenic/Likely pathogenic ★★ 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-pro21ser (accessed [today's date]).

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