Is GPHN p.Pro46Ser (c.136C>T) pathogenic?

GPHN p.Pro46Ser (c.136C>T) is classified Uncertain significance in GPHN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: likely benign (0.2328); Very rare (popmax 0.000699%, nfe); Associated with sulfite oxidase deficiency due to molybdenum cofactor deficiency type C.

What condition is associated with GPHN p.Pro46Ser (c.136C>T)?

GPHN p.Pro46Ser (c.136C>T) is associated with sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (ClinVar).

How common is GPHN p.Pro46Ser (c.136C>T) in the general population?

GPHN p.Pro46Ser (c.136C>T) is very rare (popmax 0.000699%, nfe) (gnomAD).

What do computational predictors say about GPHN p.Pro46Ser (c.136C>T)?

AlphaMissense predicts likely benign (score 0.2328) — an in-silico prediction, not a clinical call.

GPHN p.Pro46Ser

c.136C>T · rs777618122 · VCV1364281

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000699%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

Computational evidence

Protein change
AlphaMissense	0.2328	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 5.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 316 kb · p 0.99 · regional, not allelic
Overall
CADD	27.9	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 0.000699% European (non-Finnish) · 8/1,144,560 alleles

Filtering AF 0.000301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000217%

Overall 0.000508% 8/1,573,264 alleles · very rare exomes 7/1,421,212 · genomes 1/152,052 · 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: GPHN
Protein: p.Pro46Ser
Coding: c.136C>T
MANE Select: NM_020806
dbSNP: rs777618122
Type: single nucleotide variant
Location: chr14:66681178 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 84.15 · 1 PDB
Residue 46: the 'mpt mo-transferase' region; a turn

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

Disease context

sulfite oxidase deficiency due to molybdenum cofactor deficiency type C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PALS1 p.Arg46Met Uncertain significance ★ ⚠ same residue
RDH12 p.Gly46= Conflicting classifications of pathogenicity ★ same residue
RDH12 p.Gly46Ser Uncertain significance ★ ⚠ same residue
GPHN c.828+1G>A Likely pathogenic ★★ same condition
GPHN p.Tyr56Ter Pathogenic/Likely pathogenic ★★ same condition
GPHN c.1413+3A>G Uncertain significance ★★ same condition
GPHN p.Ala239Thr Uncertain significance ★★ ⚠ same condition
GPHN p.Ala448Ser 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/gphn-p-pro46ser (accessed [today's date]).

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