Is GPT2 p.Phe446Ser (c.1337T>C) pathogenic?

GPT2 p.Phe446Ser (c.1337T>C) is classified Uncertain significance in GPT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.0998); Ultra-rare (popmax 0.0213%, afr); Associated with Inborn genetic diseases.

What condition is associated with GPT2 p.Phe446Ser (c.1337T>C)?

GPT2 p.Phe446Ser (c.1337T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GPT2 p.Phe446Ser (c.1337T>C) in the general population?

GPT2 p.Phe446Ser (c.1337T>C) is ultra-rare (popmax 0.0213%, afr) (gnomAD).

What do computational predictors say about GPT2 p.Phe446Ser (c.1337T>C)?

AlphaMissense predicts likely benign (score 0.0998) — an in-silico prediction, not a clinical call.

GPT2 p.Phe446Ser

c.1337T>C · VCV3855541

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0998 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0998	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -1.62	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 6.1	GERP 0.32, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 44 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	20.5	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 0.0213% African / African-American · 16/75,080 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00124% 20/1,614,236 alleles · ultra-rare exomes 8/1,461,878 · genomes 12/152,358 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0213%	4,693
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	0.000254%	393,346

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.Phe446Ser
Coding: c.1337T>C
MANE Select: NM_133443
Type: single nucleotide variant
Location: chr16:46924513 (GRCh38)
Gene constraint: LOEUF 0.677 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.89 · 1 PDB

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.Ser124Thr Uncertain significance ★★ ⚠ same condition
GPT2 p.Tyr182Phe Uncertain significance ★★ ⚠ same condition
GPT2 p.Val163Met Uncertain significance ★★ ⚠ same condition
GPT2 p.Pro325= Likely benign ★★ 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-phe446ser (accessed [today's date]).

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