Is P4HTM p.Gln96fs (c.286dup) pathogenic?

P4HTM p.Gln96fs (c.286dup) is classified Uncertain significance in P4HTM (ClinVar, Single submitter, 2 submitters; last evaluated 2017-12-31). Very rare (popmax 0.00254%, nfe); Associated with intellectual disability.

How common is P4HTM p.Gln96fs (c.286dup) in the general population?

P4HTM p.Gln96fs (c.286dup) is very rare (popmax 0.00254%, nfe) (gnomAD).

P4HTM p.Gln96fs

Q: What condition is associated with P4HTM p.Gln96fs (c.286dup)?

P4HTM p.Gln96fs (c.286dup) is associated with intellectual disability, hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (ClinVar).

c.286dup · rs1576601503 · VCV635796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Conditions

intellectual disability

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.24	GERP -4.4
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CGAGCC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,254 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00186% 30/1,610,504 alleles · very rare exomes 29/1,458,462 · genomes 1/152,042 · 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: P4HTM
Protein: p.Gln96fs
Coding: c.286dup
MANE Select: NM_177939
dbSNP: rs1576601503
Type: Duplication
Location: chr3:48990538 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 1 PDB
Residue 96: the 'disordered' region

Full P4HTM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities

Similar variants

P4HTM c.1074-11dup Uncertain significance ★ same condition
P4HTM p.Asn274fs Likely pathogenic same condition
P4HTM p.Pro413Leu Pathogenic/Likely pathogenic ★★ same condition
P4HTM p.Trp220Ter Pathogenic ★★ same condition
P4HTM p.Ser184Thr Uncertain significance ★★ ⚠ same condition
P4HTM c.1165_1166del Likely pathogenic ★ same condition
P4HTM c.436+1G>T Likely pathogenic ★ same condition
P4HTM p.Arg358His Pathogenic ★ 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/p4htm-p-gln96fs (accessed [today's date]).

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