Is PRPH p.His412Pro (c.1235A>C) pathogenic?

PRPH p.His412Pro (c.1235A>C) is classified Uncertain significance in PRPH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-05). AlphaMissense: likely benign (0.1033); Very rare (popmax 0.00446%, eas); Associated with amyotrophic lateral sclerosis type 10.

What condition is associated with PRPH p.His412Pro (c.1235A>C)?

PRPH p.His412Pro (c.1235A>C) is associated with amyotrophic lateral sclerosis type 10 (ClinVar).

How common is PRPH p.His412Pro (c.1235A>C) in the general population?

PRPH p.His412Pro (c.1235A>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PRPH p.His412Pro (c.1235A>C)?

AlphaMissense predicts likely benign (score 0.1033) — an in-silico prediction, not a clinical call.

PRPH p.His412Pro

Q: How is Frontotemporal dementia with motor neuron disease inherited?

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

c.1235A>C · rs760653849 · VCV1801688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1033 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

amyotrophic lateral sclerosis type 10

Computational evidence

Protein change
AlphaMissense	0.1033	likely benign
REVEL	0.42	indeterminate
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 3,149 bp · p 0.024 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,856 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000124% 2/1,613,700 alleles · very rare exomes 2/1,461,440 · genomes 0/152,260 · 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: PRPH
Protein: p.His412Pro
Coding: c.1235A>C
MANE Select: NM_006262
dbSNP: rs760653849
Type: single nucleotide variant
Location: chr12:49297694 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.24
Residue 412: the 'tail' region

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

Disease context

amyotrophic lateral sclerosis type 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

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
PRPH p.Ala277Thr Likely 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-his412pro (accessed [today's date]).

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