Is TXK p.Arg241His (c.722G>A) pathogenic?

TXK p.Arg241His (c.722G>A) is classified Uncertain significance in TXK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: ambiguous (0.4796); Ultra-rare (popmax 0.0329%, mid).

How common is TXK p.Arg241His (c.722G>A) in the general population?

TXK p.Arg241His (c.722G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about TXK p.Arg241His (c.722G>A)?

AlphaMissense predicts ambiguous (score 0.4796) — an in-silico prediction, not a clinical call.

TXK p.Arg241His

c.722G>A · VCV4194255

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4796	ambiguous
REVEL	0.7	pathogenic-leaning
SaProt	LLR -10.38	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 67 kb · p 0.023 · 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 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00186% 30/1,612,738 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
East Asian	0.00892%	11,216
African / African-American	0.00401%	24,946
Remaining individualsnot grpmax-eligible	0.0016%	62,416
Finnishnot grpmax-eligible	0.00156%	63,936
European (non-Finnish)	0.00153%	65,508
South Asian	0.0011%	91,034

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: TXK
Protein: p.Arg241His
Coding: c.722G>A
MANE Select: NM_003328
Type: single nucleotide variant
Location: chr4:48089812 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.88 · 1 PDB
Residue 241: the sh2 domain

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

Similar variants

TXK p.Ala160Val Uncertain significance ★ ⚠ same type
TXK p.Ala172Ser Uncertain significance ★ ⚠ same type
TXK p.Ala192Val Uncertain significance ★ ⚠ same type
TXK p.Ala491Thr Uncertain significance ★ ⚠ same type
TXK p.Ala514Val Uncertain significance ★ ⚠ same type
TXK p.Ala519Thr Uncertain significance ★ ⚠ same type
TXK p.Ala524Glu Uncertain significance ★ ⚠ same type
TXK p.Arg291Trp 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/txk-p-arg241his (accessed [today's date]).

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