Is P4HTM p.Pro413Leu (c.1238C>T) pathogenic?

P4HTM p.Pro413Leu (c.1238C>T) is classified Pathogenic/Likely pathogenic in P4HTM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-10). AlphaMissense: likely pathogenic (0.9485); Very rare (popmax 0.000254%, nfe); Associated with intellectual disability.

What condition is associated with P4HTM p.Pro413Leu (c.1238C>T)?

P4HTM p.Pro413Leu (c.1238C>T) is associated with intellectual disability (ClinVar).

How common is P4HTM p.Pro413Leu (c.1238C>T) in the general population?

P4HTM p.Pro413Leu (c.1238C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about P4HTM p.Pro413Leu (c.1238C>T)?

AlphaMissense predicts likely pathogenic (score 0.9485) — an in-silico prediction, not a clinical call.

P4HTM p.Pro413Leu

c.1238C>T · rs757914897 · VCV981901

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.9485	likely pathogenic ✓ concordant with ClinVar
REVEL	0.732	pathogenic-leaning
SaProt	LLR -11.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 17 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,812 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00254% 41/1,612,568 alleles · very rare exomes 37/1,460,498 · genomes 4/152,070 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0572%	1,747
Remaining individualsnot grpmax-eligible	0.0032%	31,229
European (non-Finnish)grpmax	0.000254%	393,270

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro413Leu
Coding: c.1238C>T
MANE Select: NM_177939
dbSNP: rs757914897
Type: single nucleotide variant
Location: chr3:49006137 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 1 PDB
Residue 413: the fe2og dioxygenase domain

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

Similar variants

P4HTM p.His161Pro Uncertain significance ★ ⚠ same condition
P4HTM p.Gln96fs Uncertain significance ★ same condition
P4HTM p.Trp220Ter Pathogenic ★★ same type
P4HTM p.Ala233Thr Uncertain significance ★★ ⚠ same type
P4HTM p.Arg493Gln Uncertain significance ★★ ⚠ same type
P4HTM p.Ser171Gly Uncertain significance ★★ ⚠ same type
P4HTM p.Ser184Thr Uncertain significance ★★ ⚠ same type
P4HTM p.Ser269Thr Uncertain significance ★★ ⚠ same type

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-pro413leu (accessed [today's date]).

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