Is PRPH p.Asp141Tyr (c.421G>T) pathogenic?

PRPH p.Asp141Tyr (c.421G>T) is classified Conflicting classifications of pathogenicity in PRPH (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-05-20). AlphaMissense: ambiguous (0.3726); Rare (popmax 0.664%, nfe); Associated with amyotrophic lateral sclerosis.

What condition is associated with PRPH p.Asp141Tyr (c.421G>T)?

PRPH p.Asp141Tyr (c.421G>T) is associated with amyotrophic lateral sclerosis (ClinVar).

How common is PRPH p.Asp141Tyr (c.421G>T) in the general population?

PRPH p.Asp141Tyr (c.421G>T) is rare (popmax 0.664%, nfe) (gnomAD).

How is Amyotrophic lateral sclerosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRPH p.Asp141Tyr (c.421G>T)?

AlphaMissense predicts ambiguous (score 0.3726) — an in-silico prediction, not a clinical call.

PRPH p.Asp141Tyr

c.421G>T · rs58599399 · VCV13707

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.3726 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.664%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

amyotrophic lateral sclerosis

Computational evidence

Protein change
AlphaMissense	0.3726	ambiguous
REVEL	0.71	pathogenic-leaning
SaProt	LLR -9.58	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 9.8	GERP 0.71, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,149 bp · p 0.024 · regional, not allelic
Overall
CADD	33.0	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 0.664% European (non-Finnish) · 7,611/1,145,732 alleles

Filtering AF 0.652% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.647%

Overall 0.542% 8,379/1,545,564 alleles · rare exomes 7,830/1,393,228 · genomes 549/152,336 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.664%	151
Finnishnot grpmax-eligible	0.468%	213
Remaining individualsnot grpmax-eligible	0.41%	244
Admixed American	0.291%	344
African / African-American	0.116%	860
Middle Eastern	0.0516%	1,939
Ashkenazi Jewishnot grpmax-eligible	0.0385%	2,594
South Asian	0.0167%	6,001

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.Asp141Tyr
Coding: c.421G>T
MANE Select: NM_006262
dbSNP: rs58599399
Type: single nucleotide variant
Location: chr12:49295621 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.24
Residue 141: the if rod domain; a UniProt-annotated variant site (in als; uncertain significance; leads to filamentous aggregate formation); the 'linker 1' region

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

Disease context

amyotrophic lateral sclerosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Amyotrophic lateral sclerosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

PRPH p.Arg64Ter Uncertain significance ★ same condition
PRPH p.Glu233Lys Uncertain significance ★★ ⚠ same type
PRPH p.Ile419Met Uncertain significance ★★ ⚠ same type
PRPH c.1267+58T>C Benign ★★ same type
PRPH c.1268-34T>C Benign ★★ same type
PRPH c.703-163T>C Benign ★★ same type
PRPH c.996+1G>A Benign/Likely benign ★★ same type
PRPH c.-24G>C Benign ★★ same type

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-asp141tyr (accessed [today's date]).

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