Is P4HTM p.Leu162Pro (c.485T>C) pathogenic?

P4HTM p.Leu162Pro (c.485T>C) is classified Uncertain significance in P4HTM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.9956); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with P4HTM p.Leu162Pro (c.485T>C)?

P4HTM p.Leu162Pro (c.485T>C) is associated with Inborn genetic diseases (ClinVar).

How common is P4HTM p.Leu162Pro (c.485T>C) in the general population?

P4HTM p.Leu162Pro (c.485T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about P4HTM p.Leu162Pro (c.485T>C)?

AlphaMissense predicts likely pathogenic (score 0.9956) — an in-silico prediction, not a clinical call.

P4HTM p.Leu162Pro

c.485T>C · VCV4129886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9956 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9956	likely pathogenic · top 3% in P4HTM
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -14.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 17 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	29.1	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.Leu162Pro
Coding: c.485T>C
MANE Select: NM_177939
Type: single nucleotide variant
Location: chr3:49001486 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 1 PDB
Residue 162: an α-helix

Full P4HTM 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

P4HTM p.Ala233Thr Uncertain significance ★★ ⚠ same condition
P4HTM p.Arg493Gln Uncertain significance ★★ ⚠ same condition
P4HTM p.Ser171Gly Uncertain significance ★★ ⚠ same condition
P4HTM p.Ser184Thr Uncertain significance ★★ ⚠ same condition
P4HTM c.1073+105G>A Uncertain significance ★ same condition
P4HTM c.1073+16C>G Uncertain significance ★ same condition
P4HTM c.1073+36T>G Conflicting classifications of pathogenicity ★ same condition
P4HTM c.1073+38A>G Conflicting classifications of pathogenicity ★ 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-leu162pro (accessed [today's date]).

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