Is PHB2 p.Arg123His (c.368G>A) pathogenic?

PHB2 p.Arg123His (c.368G>A) is classified Uncertain significance in PHB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.1282); Very rare (popmax 0.00267%, afr).

How common is PHB2 p.Arg123His (c.368G>A) in the general population?

PHB2 p.Arg123His (c.368G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PHB2 p.Arg123His (c.368G>A)?

AlphaMissense predicts likely benign (score 0.1282) — an in-silico prediction, not a clinical call.

PHB2 p.Arg123His

c.368G>A · rs782150944 · VCV2533991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1282 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1282	likely benign
REVEL	0.314	indeterminate
SaProt	LLR -6.55	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,544 bp · p 0.00039 · regional, not allelic
Overall
CADD	25.3	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 0.00267% African / African-American · 2/74,884 alleles

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

Overall 0.000496% 8/1,612,736 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,442
Admixed American	0.00167%	59,952
Remaining individualsnot grpmax-eligible	0.0016%	62,428
European (non-Finnish)	0.000339%	294,750

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: PHB2
Protein: p.Arg123His
Coding: c.368G>A
MANE Select: NM_001144831
dbSNP: rs782150944
Type: single nucleotide variant
Location: chr12:6968520 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 85.36 · 8 PDB
Residue 123: an α-helix; the 'lc3-interaction region' region

Full PHB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHB2 p.Arg123Cys Uncertain significance ★ ⚠ same residue
PHB2 p.Ser293= Benign ★★ same type
PHB2 p.Thr274= Benign ★★ same type
PHB2 p.Ala22Val Uncertain significance ★ ⚠ same type
PHB2 p.Ala33Val Uncertain significance ★ ⚠ same type
PHB2 p.Arg191Gln Uncertain significance ★ ⚠ same type
PHB2 p.Arg209Gln Uncertain significance ★ ⚠ same type
PHB2 p.Arg222Gln 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/phb2-p-arg123his (accessed [today's date]).

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