Is BARHL1 p.Pro23Ser (c.67C>T) pathogenic?

BARHL1 p.Pro23Ser (c.67C>T) is classified Uncertain significance in BARHL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-30). AlphaMissense: likely benign (0.07); Ultra-rare (popmax 0.0245%, eas).

How common is BARHL1 p.Pro23Ser (c.67C>T) in the general population?

BARHL1 p.Pro23Ser (c.67C>T) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about BARHL1 p.Pro23Ser (c.67C>T)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

BARHL1 p.Pro23Ser

c.67C>T · rs528213989 · VCV2215315

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.3	indeterminate
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.57, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 4,719 bp · p 0.12 · regional, not allelic
Overall
CADD	21.5	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 0.0245% East Asian · 11/44,856 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00167% 27/1,612,572 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,078
Remaining individualsnot grpmax-eligible	0.0128%	7,798
European (non-Finnish)	0.000678%	147,472

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: BARHL1
Protein: p.Pro23Ser
Coding: c.67C>T
MANE Select: NM_020064
dbSNP: rs528213989
Type: single nucleotide variant
Location: chr9:132582864 (GRCh38)
Gene constraint: LOEUF 0.419 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.80
Residue 23: the 'disordered' region

Full BARHL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BARHL1 p.Ala112Glu Uncertain significance ★ ⚠ same type
BARHL1 p.Ala130Val Uncertain significance ★ ⚠ same type
BARHL1 p.Ala17Thr Uncertain significance ★ ⚠ same type
BARHL1 p.Ala213Thr Uncertain significance ★ ⚠ same type
BARHL1 p.Ala276Val Uncertain significance ★ ⚠ same type
BARHL1 p.Ala52Thr Uncertain significance ★ ⚠ same type
BARHL1 p.Ala85Val Uncertain significance ★ ⚠ same type
BARHL1 p.Arg174Leu 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/barhl1-p-pro23ser (accessed [today's date]).

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