Is CHL1 p.Pro724= (c.2172A>G) pathogenic?

CHL1 p.Pro724= (c.2172A>G) is classified Likely benign in CHL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-11). Ultra-rare (popmax 0.0109%, nfe); Associated with CHL1-related disorder.

What condition is associated with CHL1 p.Pro724= (c.2172A>G)?

CHL1 p.Pro724= (c.2172A>G) is associated with CHL1-related disorder (ClinVar).

How common is CHL1 p.Pro724= (c.2172A>G) in the general population?

CHL1 p.Pro724= (c.2172A>G) is ultra-rare (popmax 0.0109%, nfe) (gnomAD).

CHL1 p.Pro724=

c.2172A>G · rs199513859 · VCV3057254

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, nfe)

Conditions

CHL1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.7	GERP -3.3
Overall
CADD	0.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% European (non-Finnish) · 128/1,178,818 alleles

Filtering AF 0.00928% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00872%

Overall 0.00856% 138/1,612,580 alleles · ultra-rare exomes 131/1,460,428 · genomes 7/152,152 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,921
European (non-Finnish)grpmax	0.0109%	9,210
East Asian	0.00223%	44,866
Finnishnot grpmax-eligible	0.00156%	64,020
African / African-American	0.00134%	74,886

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CHL1
Protein: p.Pro724=
Coding: c.2172A>G
MANE Select: NM_006614
dbSNP: rs199513859
Type: single nucleotide variant
Location: chr3:382667 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.37
Residue 724: the fibronectin type-iii 2 domain

Full CHL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CHL1-related disorder

Similar variants

CHL1 p.Leu253Gln Uncertain significance ★ same condition
CHL1 p.Asn192Lys Uncertain significance ⚠ same condition
CHL1 c.679+7C>T Likely benign same condition
CHL1 p.Arg885= Likely benign same condition
CHL1 p.His1188= Likely benign same condition
CHL1 p.Ile1035Thr Likely benign same condition
CHL1 p.Leu17Phe Benign same condition
CHL1 p.Tyr52Cys Likely benign same condition

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/chl1-p-pro724 (accessed [today's date]).

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