Is GNPAT p.Pro657Arg (c.1970C>G) pathogenic?

GNPAT p.Pro657Arg (c.1970C>G) is classified Uncertain significance in GNPAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely benign (0.0866); Very rare (popmax 9.9e-05%, nfe).

How common is GNPAT p.Pro657Arg (c.1970C>G) in the general population?

GNPAT p.Pro657Arg (c.1970C>G) is very rare (popmax 9.9e-05%, nfe) (gnomAD).

What do computational predictors say about GNPAT p.Pro657Arg (c.1970C>G)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

GNPAT p.Pro657Arg

c.1970C>G · rs2102829062 · VCV1475855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.9e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0866	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -6.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 2.4, phastCons 0.71
Regional constraint	o/e 0.88	unconstrained · MANE · 36 kb · p 0.00057 · regional, not allelic
Overall
CADD	19.68	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 9.9e-05% European (non-Finnish) · 1/1,010,300 alleles

Overall 7.01e-05% 1/1,426,204 alleles · very rare exomes 1/1,274,014 · genomes 0/152,190 · 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: GNPAT
Protein: p.Pro657Arg
Coding: c.1970C>G
MANE Select: NM_014236
dbSNP: rs2102829062
Type: single nucleotide variant
Location: chr1:231276167 (GRCh38)
Gene constraint: LOEUF 0.572 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 88.96

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

Similar variants

GNPAT p.Pro657= Likely benign ★★ same residue
GNPAT p.Pro657Thr Uncertain significance ★ ⚠ same residue
GNPAT c.569-3T>G Pathogenic ★★ same type
GNPAT p.Arg163Ter Pathogenic ★★ same type
GNPAT p.Arg211Cys Likely pathogenic ★★ same type
GNPAT p.Arg211His Pathogenic ★★ same type
GNPAT p.Arg335Ter Likely pathogenic ★★ same type
GNPAT p.Trp386Ter Pathogenic/Likely pathogenic ★★ 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/gnpat-p-pro657arg (accessed [today's date]).

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