Is TYR p.Pro412Ala (c.1234C>G) pathogenic?

TYR p.Pro412Ala (c.1234C>G) is classified Conflicting classifications of pathogenicity in TYR (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-18). AlphaMissense: ambiguous (0.3939); Very rare (popmax 0.000255%, nfe); Associated with TYR-related disorder.

What condition is associated with TYR p.Pro412Ala (c.1234C>G)?

TYR p.Pro412Ala (c.1234C>G) is associated with TYR-related disorder, oculocutaneous albinism type 1A (ClinVar).

How common is TYR p.Pro412Ala (c.1234C>G) in the general population?

TYR p.Pro412Ala (c.1234C>G) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about TYR p.Pro412Ala (c.1234C>G)?

AlphaMissense predicts ambiguous (score 0.3939) — an in-silico prediction, not a clinical call.

TYR p.Pro412Ala

c.1234C>G · rs797046081 · VCV212521

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

TYR-related disorder

Computational evidence

Protein change
AlphaMissense	0.3939	ambiguous
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -10.02	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 117 kb · p 0.00089 · regional, not allelic
Overall
CADD	25.7	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 0.000255% European (non-Finnish) · 3/1,178,536 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,611,876 alleles · very rare exomes 3/1,459,938 · genomes 0/151,938 · joint denominator

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.Pro412Ala
Coding: c.1234C>G
MANE Select: NM_000372
dbSNP: rs797046081
Type: single nucleotide variant
Location: chr11:89284822 (GRCh38)
Gene constraint: LOEUF 1.346 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79 · 1 PDB

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

Disease context

TYR-related disorder

Also linked: oculocutaneous albinism type 1A

Similar variants

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
TYR c.1185-2A>G Pathogenic/Likely pathogenic ★★ same condition
TYR c.1366+1G>T 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-pro412ala (accessed [today's date]).

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