Is BARHL1 p.Pro54Arg (c.161C>G) pathogenic?

BARHL1 p.Pro54Arg (c.161C>G) is classified Uncertain significance in BARHL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-07). AlphaMissense: likely benign (0.1017); Very rare (popmax 0.00267%, afr).

How common is BARHL1 p.Pro54Arg (c.161C>G) in the general population?

BARHL1 p.Pro54Arg (c.161C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about BARHL1 p.Pro54Arg (c.161C>G)?

AlphaMissense predicts likely benign (score 0.1017) — an in-silico prediction, not a clinical call.

BARHL1 p.Pro54Arg

c.161C>G · rs371086101 · VCV2300016

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1017	likely benign
REVEL	0.758	pathogenic-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 4,719 bp · p 0.12 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,944 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,804 alleles · very rare

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.Pro54Arg
Coding: c.161C>G
MANE Select: NM_020064
dbSNP: rs371086101
Type: single nucleotide variant
Location: chr9:132582958 (GRCh38)
Gene constraint: LOEUF 0.419 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.80
Residue 54: 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-pro54arg (accessed [today's date]).

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