Is GPHN p.Ser663Pro (c.1987T>C) pathogenic?

GPHN p.Ser663Pro (c.1987T>C) is classified Uncertain significance in GPHN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-11). AlphaMissense: likely pathogenic (0.9985); Very rare (popmax 0.000766%, nfe); Associated with sulfite oxidase deficiency due to molybdenum cofactor deficiency type C.

What condition is associated with GPHN p.Ser663Pro (c.1987T>C)?

GPHN p.Ser663Pro (c.1987T>C) is associated with sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (ClinVar).

How common is GPHN p.Ser663Pro (c.1987T>C) in the general population?

GPHN p.Ser663Pro (c.1987T>C) is very rare (popmax 0.000766%, nfe) (gnomAD).

What do computational predictors say about GPHN p.Ser663Pro (c.1987T>C)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

GPHN p.Ser663Pro

c.1987T>C · rs762085852 · VCV1444945

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000766%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -11.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 110 kb · p 7.9e-10 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S630P vs ClinVar S663P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000766% European (non-Finnish) · 9/1,174,784 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000995% 16/1,608,428 alleles · very rare exomes 16/1,456,112 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00781%	12,804
Remaining individualsnot grpmax-eligible	0.00321%	31,151
European (non-Finnish)grpmax	0.000766%	130,532

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser663Pro
Coding: c.1987T>C
MANE Select: NM_020806
dbSNP: rs762085852
Type: single nucleotide variant
Location: chr14:67168944 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 84.15 · 1 PDB
Residue 630 UniProt numbering: the 'mpt adenylyltransferase' 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.Ser663= Likely 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
GPHN p.Ala590Ser 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-ser663pro (accessed [today's date]).

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