Is P4HTM p.Ser189Arg (c.567C>G) pathogenic?

P4HTM p.Ser189Arg (c.567C>G) is classified Uncertain significance in P4HTM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: ambiguous (0.5372); Very rare (popmax 0.00934%, afr); Associated with Inborn genetic diseases.

What condition is associated with P4HTM p.Ser189Arg (c.567C>G)?

P4HTM p.Ser189Arg (c.567C>G) is associated with Inborn genetic diseases (ClinVar).

How common is P4HTM p.Ser189Arg (c.567C>G) in the general population?

P4HTM p.Ser189Arg (c.567C>G) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about P4HTM p.Ser189Arg (c.567C>G)?

AlphaMissense predicts ambiguous (score 0.5372) — an in-silico prediction, not a clinical call.

P4HTM p.Ser189Arg

c.567C>G · rs149345145 · VCV3207780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5372 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5372	ambiguous
REVEL	0.52	indeterminate
SaProt	LLR -10.14	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 17 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	26.7	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 0.00934% African / African-American · 7/74,936 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,613,604 alleles · very rare exomes 3/1,461,368 · genomes 4/152,236 · 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.Ser189Arg
Coding: c.567C>G
MANE Select: NM_177939
dbSNP: rs149345145
Type: single nucleotide variant
Location: chr3:49001568 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 1 PDB
Residue 189: the ef-hand 1 domain

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-ser189arg (accessed [today's date]).

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