Is GPT2 p.Pro325= (c.975C>T) pathogenic?

GPT2 p.Pro325= (c.975C>T) is classified Likely benign in GPT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-02). Ultra-rare (popmax 0.0624%, eas); Associated with Inborn genetic diseases.

What condition is associated with GPT2 p.Pro325= (c.975C>T)?

GPT2 p.Pro325= (c.975C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GPT2 p.Pro325= (c.975C>T) in the general population?

GPT2 p.Pro325= (c.975C>T) is ultra-rare (popmax 0.0624%, eas) (gnomAD).

GPT2 p.Pro325=

c.975C>T · rs569695348 · VCV1675622

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.2
Overall
CADD	2.742	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0624% East Asian · 28/44,882 alleles

Filtering AF 0.0443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0382%

Overall 0.0044% 71/1,614,210 alleles · ultra-rare exomes 60/1,461,868 · genomes 11/152,342 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0624%	1,603
Middle Eastern	0.0165%	6,062
African / African-American	0.00799%	12,511
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)	0.00254%	39,334
Admixed American	0.00167%	60,024

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: GPT2
Protein: p.Pro325=
Coding: c.975C>T
MANE Select: NM_133443
dbSNP: rs569695348
Type: single nucleotide variant
Location: chr16:46918695 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.89 · 1 PDB
Residue 325: an α-helix

Full GPT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GPT2 p.Arg110Trp Uncertain significance ★★ ⚠ same condition
GPT2 p.Phe446Ser Uncertain significance ★★ ⚠ same condition
GPT2 p.Ser124Thr Uncertain significance ★★ ⚠ same condition
GPT2 p.Tyr182Phe Uncertain significance ★★ ⚠ same condition
GPT2 p.Val163Met Uncertain significance ★★ ⚠ same condition
GPT2 p.Gln24Ter Pathogenic ★ same condition
GPT2 p.Ser153Arg Likely pathogenic ★ same condition
GPT2 c.1037+5G>C 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/gpt2-p-pro325 (accessed [today's date]).

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