Is HOMER2 p.Arg208Cys (c.622C>T) pathogenic?

HOMER2 p.Arg208Cys (c.622C>T) is classified Uncertain significance in HOMER2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-14). AlphaMissense: likely benign (0.1399); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with HOMER2 p.Arg208Cys (c.622C>T)?

HOMER2 p.Arg208Cys (c.622C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HOMER2 p.Arg208Cys (c.622C>T) in the general population?

HOMER2 p.Arg208Cys (c.622C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about HOMER2 p.Arg208Cys (c.622C>T)?

AlphaMissense predicts likely benign (score 0.1399) — an in-silico prediction, not a clinical call.

HOMER2 p.Arg208Cys

c.622C>T · VCV3858303

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1399 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1399	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 103 kb · p 0.7 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R219C vs ClinVar R208C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,974 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00155% 25/1,612,826 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,993
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)	0.00153%	65,546
African / African-American	0.00133%	74,914
South Asian	0.0011%	91,032

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: HOMER2
Protein: p.Arg208Cys
Coding: c.622C>T
MANE Select: NM_004839
Type: single nucleotide variant
Location: chr15:82854673 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.20

Full HOMER2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HOMER2 p.Arg208His Benign ★★ ⚠ same residue
CPD p.Arg208Pro Uncertain significance ★ ⚠ same residue
HOMER2 p.Arg215His Uncertain significance ★★ ⚠ same condition
HOMER2 p.Arg334Gln Uncertain significance ★★ ⚠ same condition
HOMER2 p.Asn235Lys Uncertain significance ★★ ⚠ same condition
HOMER2 p.Glu255Asp Uncertain significance ★★ ⚠ same condition
HOMER2 p.Glu274Lys Uncertain significance ★★ ⚠ same condition
HOMER2 p.Gly335Glu Uncertain significance ★★ ⚠ same condition

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/homer2-p-arg208cys (accessed [today's date]).

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