Is ERBB4 p.Pro557Ser (c.1669C>T) pathogenic?

ERBB4 p.Pro557Ser (c.1669C>T) is classified Uncertain significance in ERBB4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-28). AlphaMissense: likely benign (0.0777); Ultra-rare (popmax 0.0115%, nfe); Associated with ERBB4-related disorder.

What condition is associated with ERBB4 p.Pro557Ser (c.1669C>T)?

ERBB4 p.Pro557Ser (c.1669C>T) is associated with ERBB4-related disorder (ClinVar).

How common is ERBB4 p.Pro557Ser (c.1669C>T) in the general population?

ERBB4 p.Pro557Ser (c.1669C>T) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

What do computational predictors say about ERBB4 p.Pro557Ser (c.1669C>T)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

ERBB4 p.Pro557Ser

c.1669C>T · rs771809161 · VCV2187479

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ERBB4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.87 · regional, not allelic
Overall
CADD	16.0	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 0.0115% European (non-Finnish) · 136/1,179,772 alleles

Filtering AF 0.00994% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00931%

Overall 0.00905% 146/1,613,532 alleles · ultra-rare exomes 140/1,461,636 · genomes 6/151,896 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,675
Admixed American	0.00834%	11,992
Remaining individualsnot grpmax-eligible	0.0064%	15,617
African / African-American	0.00134%	74,822

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: ERBB4
Protein: p.Pro557Ser
Coding: c.1669C>T
MANE Select: NM_005235
dbSNP: rs771809161
Type: single nucleotide variant
Location: chr2:211673211 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.17 · 14 PDB

Full ERBB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ERBB4-related disorder

Similar variants

ERBB4 p.Arg1175Ser Uncertain significance ★★ same condition
ERBB4 p.Gly1061Glu Uncertain significance ★★ ⚠ same condition
ERBB4 p.Ile666Thr Uncertain significance ★★ ⚠ same condition
ERBB4 p.Ile892Val Uncertain significance ★★ ⚠ same condition
ERBB4 p.Ser464Arg Uncertain significance ★★ ⚠ same condition
ERBB4 c.2719+4A>T Uncertain significance ★ same condition
ERBB4 p.Arg47Gln Uncertain significance ★ ⚠ same condition
ERBB4 p.Asp518Glu 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/erbb4-p-pro557ser (accessed [today's date]).

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