Is GPHN p.Pro92Ser (c.274C>T) pathogenic?

GPHN p.Pro92Ser (c.274C>T) is classified Uncertain significance in GPHN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). AlphaMissense: likely pathogenic (0.6632); Very rare (popmax 8.91e-05%, nfe); Associated with sulfite oxidase deficiency due to molybdenum cofactor deficiency type C.

What condition is associated with GPHN p.Pro92Ser (c.274C>T)?

GPHN p.Pro92Ser (c.274C>T) is associated with sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (ClinVar).

How common is GPHN p.Pro92Ser (c.274C>T) in the general population?

GPHN p.Pro92Ser (c.274C>T) is very rare (popmax 8.91e-05%, nfe) (gnomAD).

What do computational predictors say about GPHN p.Pro92Ser (c.274C>T)?

AlphaMissense predicts likely pathogenic (score 0.6632) — an in-silico prediction, not a clinical call.

GPHN p.Pro92Ser

c.274C>T · rs937919465 · VCV2767436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6632 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.91e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

Computational evidence

Protein change
AlphaMissense	0.6632	likely pathogenic
REVEL	0.578	indeterminate
SaProt	LLR -13.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 98 kb · p 1.7e-07 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.91e-05% European (non-Finnish) · 1/1,122,394 alleles

Overall 6.45e-05% 1/1,550,816 alleles · very rare exomes 1/1,398,598 · genomes 0/152,218 · 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.Pro92Ser
Coding: c.274C>T
MANE Select: NM_020806
dbSNP: rs937919465
Type: single nucleotide variant
Location: chr14:66824546 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 84.15 · 1 PDB
Residue 92: the 'mpt mo-transferase' region

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

GPHN p.Pro92Ala Uncertain significance ★ same residue
PIGH p.Ile92= Benign 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
GPHN p.Ala55Ser 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-pro92ser (accessed [today's date]).

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