Is PHB2 p.Arg209Gln (c.626G>A) pathogenic?

PHB2 p.Arg209Gln (c.626G>A) is classified Uncertain significance in PHB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.8825); Very rare (popmax 0.00271%, nfe).

How common is PHB2 p.Arg209Gln (c.626G>A) in the general population?

PHB2 p.Arg209Gln (c.626G>A) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about PHB2 p.Arg209Gln (c.626G>A)?

AlphaMissense predicts likely pathogenic (score 0.8825) — an in-silico prediction, not a clinical call.

PHB2 p.Arg209Gln

c.626G>A · VCV4135518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8825 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8825	likely pathogenic
REVEL	0.416	indeterminate
SaProt	LLR -9.50	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
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 0.80	unconstrained · MANE · 4,544 bp · p 0.00039 · regional, not allelic
Overall
CADD	33.0	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 0.00271% European (non-Finnish) · 32/1,179,858 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00242% 39/1,613,770 alleles · very rare exomes 37/1,461,562 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,232
European (non-Finnish)grpmax	0.00271%	36,871
South Asian	0.0022%	45,537
Admixed American	0.00167%	60,000
Finnishnot grpmax-eligible	0.00156%	63,956
African / African-American	0.00133%	74,930

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: PHB2
Protein: p.Arg209Gln
Coding: c.626G>A
MANE Select: NM_001144831
Type: single nucleotide variant
Location: chr12:6967761 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 85.36 · 8 PDB
Residue 209: an α-helix

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

Similar variants

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.Arg123Cys Uncertain significance ★ ⚠ same type
PHB2 p.Arg123His Uncertain significance ★ ⚠ same type
PHB2 p.Arg191Gln 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-arg209gln (accessed [today's date]).

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