Is CHL1 p.Ser997Pro (c.2989T>C) pathogenic?

CHL1 p.Ser997Pro (c.2989T>C) is classified Uncertain significance in CHL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.1732); Ultra-rare (popmax 0.0125%, nfe).

How common is CHL1 p.Ser997Pro (c.2989T>C) in the general population?

CHL1 p.Ser997Pro (c.2989T>C) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about CHL1 p.Ser997Pro (c.2989T>C)?

AlphaMissense predicts likely benign (score 0.1732) — an in-silico prediction, not a clinical call.

CHL1 p.Ser997Pro

c.2989T>C · VCV4228155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1732	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -8.58	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 0.54	GERP 0.34, phastCons 0.026
Regional constraint	o/e 1.25	unconstrained · MANE · 86 kb · p 2e-21 · regional, not allelic
Overall
CADD	16.27	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S981P vs ClinVar S997P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0125% European (non-Finnish) · 148/1,179,928 alleles

Filtering AF 0.0109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.0096% 155/1,613,868 alleles · ultra-rare exomes 140/1,461,768 · genomes 15/152,100 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	7,973
African / African-American	0.00668%	14,976
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Ser997Pro
Coding: c.2989T>C
MANE Select: NM_006614
Type: single nucleotide variant
Location: chr3:394767 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.37
Residue 981 UniProt numbering: the fibronectin type-iii 4 domain

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

Similar variants

CHL1 p.Ile100Val Uncertain significance ★★ ⚠ same type
CHL1 c.1306+10C>T Benign ★★ same type
CHL1 c.197+10G>C Benign ★★ same type
CHL1 p.Ala1105Val Likely benign ★★ same type
CHL1 p.Ala450= Likely benign ★★ same type
CHL1 p.Ala465= Benign ★★ same type
CHL1 p.Arg93= Benign/Likely benign ★★ same type
CHL1 p.Gln216= Benign ★★ 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/chl1-p-ser997pro (accessed [today's date]).

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