Is P4HTM p.Arg255Gln (c.764G>A) pathogenic?

P4HTM p.Arg255Gln (c.764G>A) is classified Uncertain significance in P4HTM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). AlphaMissense: likely benign (0.0793); Ultra-rare (popmax 0.0188%, mid).

How common is P4HTM p.Arg255Gln (c.764G>A) in the general population?

P4HTM p.Arg255Gln (c.764G>A) is ultra-rare (popmax 0.0188%, mid) (gnomAD).

What do computational predictors say about P4HTM p.Arg255Gln (c.764G>A)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

P4HTM p.Arg255Gln

c.764G>A · VCV4962536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.41	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 3.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 17 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	24.9	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 0.0188% Middle Eastern · 1/5,320 alleles

Filtering AF 0.00261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00152%

Overall 0.00219% 34/1,554,480 alleles · ultra-rare exomes 32/1,402,194 · genomes 2/152,286 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0188%	5,320
Admixed American	0.00776%	12,881
Remaining individualsnot grpmax-eligible	0.00498%	20,084
East Asian	0.00486%	20,565
South Asian	0.00237%	42,110
European (non-Finnish)	0.00183%	54,732
African / African-American	0.00136%	73,284

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.Arg255Gln
Coding: c.764G>A
MANE Select: NM_177939
Type: single nucleotide variant
Location: chr3:49004137 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 1 PDB
Residue 255: an α-helix; the ef-hand 2 domain

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

Similar variants

P4HTM p.Arg255Trp 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
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-arg255gln (accessed [today's date]).

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