Is P4HTM p.Arg299His (c.896G>A) pathogenic?

P4HTM p.Arg299His (c.896G>A) is classified Uncertain significance in P4HTM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-09). AlphaMissense: likely benign (0.0775); Very rare (popmax 0.00167%, amr).

How common is P4HTM p.Arg299His (c.896G>A) in the general population?

P4HTM p.Arg299His (c.896G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about P4HTM p.Arg299His (c.896G>A)?

AlphaMissense predicts likely benign (score 0.0775) — an in-silico prediction, not a clinical call.

P4HTM p.Arg299His

c.896G>A · VCV4962538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0775 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0775	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 0.24, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 17 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00167% Admixed American · 1/59,958 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000808% 13/1,607,988 alleles · very rare exomes 13/1,455,674 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,958
African / African-American	0.00133%	75,032
European (non-Finnish)	0.000933%	107,149

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.Arg299His
Coding: c.896G>A
MANE Select: NM_177939
Type: single nucleotide variant
Location: chr3:49004869 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 1 PDB
Residue 299: an α-helix

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

Similar variants

P4HTM p.Arg299Cys Uncertain significance ★ ⚠ same residue
P4HTM p.Arg299Leu Uncertain significance ★ ⚠ same residue
P4HTM p.Pro413Leu Pathogenic/Likely pathogenic ★★ same type
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

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-arg299his (accessed [today's date]).

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