Is TXK p.Ala172Ser (c.514G>T) pathogenic?

TXK p.Ala172Ser (c.514G>T) is classified Uncertain significance in TXK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-19). AlphaMissense: likely benign (0.1115); Ultra-rare (popmax 0.0254%, nfe).

How common is TXK p.Ala172Ser (c.514G>T) in the general population?

TXK p.Ala172Ser (c.514G>T) is ultra-rare (popmax 0.0254%, nfe) (gnomAD).

What do computational predictors say about TXK p.Ala172Ser (c.514G>T)?

AlphaMissense predicts likely benign (score 0.1115) — an in-silico prediction, not a clinical call.

TXK p.Ala172Ser

c.514G>T · rs139867783 · VCV2213181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1115 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1115	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -2.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.7	GERP 4.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 67 kb · p 0.023 · regional, not allelic
Overall
CADD	19.8	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 0.0254% European (non-Finnish) · 299/1,179,434 alleles

Filtering AF 0.023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.022%

Overall 0.0195% 315/1,613,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0254%	3,945
Remaining individualsnot grpmax-eligible	0.0208%	4,804
African / African-American	0.00267%	37,443
South Asian	0.0011%	91,048

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.Ala172Ser
Coding: c.514G>T
MANE Select: NM_003328
dbSNP: rs139867783
Type: single nucleotide variant
Location: chr4:48095210 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.88 · 1 PDB
Residue 172: 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.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.Arg241His 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-ala172ser (accessed [today's date]).

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