Is TSEN34 p.Lys124Arg (c.371A>G) pathogenic?

TSEN34 p.Lys124Arg (c.371A>G) is classified Uncertain significance in TSEN34 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: likely benign (0.0814); Ultra-rare (popmax 0.0165%, mid).

How common is TSEN34 p.Lys124Arg (c.371A>G) in the general population?

TSEN34 p.Lys124Arg (c.371A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TSEN34 p.Lys124Arg (c.371A>G)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

TSEN34 p.Lys124Arg

c.371A>G · VCV4708943

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -4.08	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 3.9	GERP 0.27, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 1,994 bp · p 0.0019 · regional, not allelic
Overall
CADD	16.17	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00167% 27/1,614,188 alleles · ultra-rare exomes 21/1,461,880 · genomes 6/152,308 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.0132%	7,590
African / African-American	0.00533%	18,762
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.000593%	168,575

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: TSEN34
Protein: p.Lys124Arg
Coding: c.371A>G
MANE Select: NM_001077446
Type: single nucleotide variant
Location: chr19:54191848 (GRCh38)
Gene constraint: LOEUF 1.159 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.74 · 6 PDB
Residue 124: the 'disordered' region; an α-helix

Full TSEN34 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TSEN34 p.Arg253His Uncertain significance ★★ ⚠ same type
TSEN34 p.Arg25Cys Uncertain significance ★★ ⚠ same type
TSEN34 p.Arg88Cys Uncertain significance ★★ ⚠ same type
TSEN34 p.Asp148Tyr Uncertain significance ★★ ⚠ same type
TSEN34 p.Gly39Arg Uncertain significance ★★ ⚠ same type
TSEN34 p.Ile116Phe Uncertain significance ★★ ⚠ same type
TSEN34 p.Leu227Val Uncertain significance ★★ ⚠ same type
TSEN34 p.Leu2Pro 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/tsen34-p-lys124arg (accessed [today's date]).

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