Is PRPH p.Ser28Tyr (c.83C>A) pathogenic?

PRPH p.Ser28Tyr (c.83C>A) is classified Uncertain significance in PRPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: likely benign (0.2382); Very rare (popmax 0.00834%, amr); Associated with Inborn genetic diseases.

What condition is associated with PRPH p.Ser28Tyr (c.83C>A)?

PRPH p.Ser28Tyr (c.83C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PRPH p.Ser28Tyr (c.83C>A) in the general population?

PRPH p.Ser28Tyr (c.83C>A) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about PRPH p.Ser28Tyr (c.83C>A)?

AlphaMissense predicts likely benign (score 0.2382) — an in-silico prediction, not a clinical call.

PRPH p.Ser28Tyr

c.83C>A · VCV4145053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2382 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2382	likely benign
REVEL	0.461	indeterminate
SaProt	LLR -11.04	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,149 bp · p 0.024 · regional, not allelic
Overall
CADD	26.7	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 0.00834% Admixed American · 5/59,952 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000745% 12/1,611,710 alleles · very rare exomes 10/1,459,468 · genomes 2/152,242 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,990
European (non-Finnish)	0.000593%	168,528

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: PRPH
Protein: p.Ser28Tyr
Coding: c.83C>A
MANE Select: NM_006262
Type: single nucleotide variant
Location: chr12:49295283 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.24
Residue 28: a modified residue (phosphoserine); the 'head' region

Full PRPH 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

PRPH p.Glu233Lys Uncertain significance ★★ ⚠ same condition
PRPH p.Ile419Met Uncertain significance ★★ ⚠ same condition
PRPH p.Ala109Val Uncertain significance ★ ⚠ same condition
PRPH p.Ala132Thr Uncertain significance ★ ⚠ same condition
PRPH p.Ala132Val Uncertain significance ★ ⚠ same condition
PRPH p.Ala193Glu Uncertain significance ★ ⚠ same condition
PRPH p.Ala193Gly Uncertain significance ★ ⚠ same condition
PRPH p.Ala49Val 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/prph-p-ser28tyr (accessed [today's date]).

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