Is TYR p.Ala355Pro (c.1063G>C) pathogenic?

TYR p.Ala355Pro (c.1063G>C) is classified Conflicting classifications of pathogenicity in TYR (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-08-01). AlphaMissense: ambiguous (0.4767); Very rare (popmax 0.00334%, amr); Associated with congenital nystagmus.

What condition is associated with TYR p.Ala355Pro (c.1063G>C)?

TYR p.Ala355Pro (c.1063G>C) is associated with congenital nystagmus, oculocutaneous albinism type 1A, albinism (ClinVar).

How common is TYR p.Ala355Pro (c.1063G>C) in the general population?

TYR p.Ala355Pro (c.1063G>C) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about TYR p.Ala355Pro (c.1063G>C)?

AlphaMissense predicts ambiguous (score 0.4767) — an in-silico prediction, not a clinical call.

TYR p.Ala355Pro

c.1063G>C · rs62645908 · VCV99528

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.4767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

congenital nystagmus

Computational evidence

Protein change
AlphaMissense	0.4767	ambiguous
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -4.73	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, 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 0.00334% Admixed American · 2/59,854 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00124% 20/1,612,982 alleles · very rare exomes 13/1,461,068 · genomes 7/151,914 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,927
European (non-Finnish)	0.00144%	69,392
African / African-American	0.00134%	74,814

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.Ala355Pro
Coding: c.1063G>C
MANE Select: NM_000372
dbSNP: rs62645908
Type: single nucleotide variant
Location: chr11:89227849 (GRCh38)
Gene constraint: LOEUF 1.346 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79 · 1 PDB
Residue 355: a UniProt-annotated variant site (in oca1a)

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

Disease context

congenital nystagmus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: oculocutaneous albinism type 1A albinism

Similar variants

TYR p.Ala355Val Conflicting classifications of pathogenicity ★ ⚠ same residue
TYR p.Ala355Gly Likely pathogenic ★ ⚠ same residue
TYR p.Ala355= Conflicting classifications of pathogenicity ★ same residue
TYR p.Ala355Glu Uncertain significance ★ ⚠ same residue
TYR p.Ala355Ser 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

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-ala355pro (accessed [today's date]).

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