Is CHTOP p.Leu126Gln (c.377T>A) pathogenic?

CHTOP p.Leu126Gln (c.377T>A) is classified Uncertain significance in CHTOP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely benign (0.2535); Very rare (popmax 0.00178%, nfe).

How common is CHTOP p.Leu126Gln (c.377T>A) in the general population?

CHTOP p.Leu126Gln (c.377T>A) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about CHTOP p.Leu126Gln (c.377T>A)?

AlphaMissense predicts likely benign (score 0.2535) — an in-silico prediction, not a clinical call.

CHTOP p.Leu126Gln

c.377T>A · VCV4002881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2535 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2535	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -7.73	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 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 2,861 bp · p 0.37 · regional, not allelic
Overall
CADD	22.2	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 0.00178% European (non-Finnish) · 21/1,179,740 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00136% 22/1,613,618 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,178
African / African-American	0.00133%	74,918

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: CHTOP
Protein: p.Leu126Gln
Coding: c.377T>A
MANE Select: NM_015607
Type: single nucleotide variant
Location: chr1:153642403 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.64

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

Similar variants

CHTOP p.Leu126Pro Uncertain significance ★ ⚠ same residue
CHTOP p.Ala99Ser Uncertain significance ★ ⚠ same type
CHTOP p.Arg110Lys Uncertain significance ★ ⚠ same type
CHTOP p.Arg124Thr Uncertain significance ★ ⚠ same type
CHTOP p.Arg157Gln Uncertain significance ★ ⚠ same type
CHTOP p.Arg159His Uncertain significance ★ ⚠ same type
CHTOP p.Arg169His Uncertain significance ★ ⚠ same type
CHTOP p.Arg187Trp 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/chtop-p-leu126gln (accessed [today's date]).

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