Is P4HTM p.His161Pro (c.482A>C) pathogenic?

P4HTM p.His161Pro (c.482A>C) is classified Uncertain significance in P4HTM (ClinVar, Single submitter, 2 submitters; last evaluated 2017-12-31). AlphaMissense: likely pathogenic (0.8129); Absent from gnomAD v4.1; Associated with intellectual disability.

How common is P4HTM p.His161Pro (c.482A>C) in the general population?

P4HTM p.His161Pro (c.482A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about P4HTM p.His161Pro (c.482A>C)?

AlphaMissense predicts likely pathogenic (score 0.8129) — an in-silico prediction, not a clinical call.

P4HTM p.His161Pro

Q: What condition is associated with P4HTM p.His161Pro (c.482A>C)?

P4HTM p.His161Pro (c.482A>C) is associated with intellectual disability, hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (ClinVar).

c.482A>C · rs1576606484 · VCV635795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8129 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.8129	likely pathogenic
REVEL	0.527	indeterminate
SaProt	LLR -13.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 17 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	27.2	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: P4HTM
Protein: p.His161Pro
Coding: c.482A>C
MANE Select: NM_177939
dbSNP: rs1576606484
Type: single nucleotide variant
Location: chr3:49001483 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 1 PDB
Residue 161: a UniProt-annotated variant site (in hidea); an α-helix

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 p.Pro413Leu Pathogenic/Likely pathogenic ★★ same condition
P4HTM p.Trp220Ter Pathogenic ★★ same condition
P4HTM p.Ser184Thr Uncertain significance ★★ ⚠ same condition
P4HTM c.436+1G>T Likely pathogenic ★ same condition
P4HTM p.Arg358His Pathogenic ★ same condition
P4HTM p.Glu312Lys Likely pathogenic ★ ⚠ same condition
P4HTM p.Thr361Ile Likely pathogenic ★ same condition
P4HTM c.888-156C>T 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/p4htm-p-his161pro (accessed [today's date]).

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