Is EPHB3 p.Arg326His (c.977G>A) pathogenic?

EPHB3 p.Arg326His (c.977G>A) is classified Uncertain significance in EPHB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely pathogenic (0.7841); Very rare (popmax 0.00267%, afr).

How common is EPHB3 p.Arg326His (c.977G>A) in the general population?

EPHB3 p.Arg326His (c.977G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about EPHB3 p.Arg326His (c.977G>A)?

AlphaMissense predicts likely pathogenic (score 0.7841) — an in-silico prediction, not a clinical call.

EPHB3 p.Arg326His

c.977G>A · rs1389820335 · VCV3089676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7841	likely pathogenic
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -12.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 19 kb · p 2.4e-21 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 · 2/74,918 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00118% 19/1,613,590 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,459
East Asian	0.00223%	44,856
Remaining individualsnot grpmax-eligible	0.0016%	62,446
Finnishnot grpmax-eligible	0.00156%	63,972
European (non-Finnish)	0.0011%	90,755
South Asian	0.0011%	91,038

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: EPHB3
Protein: p.Arg326His
Coding: c.977G>A
MANE Select: NM_004443
dbSNP: rs1389820335
Type: single nucleotide variant
Location: chr3:184575950 (GRCh38)
Gene constraint: LOEUF 0.435 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.62 · 4 PDB

Full EPHB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHB3 p.Arg326Ser Uncertain significance ★ ⚠ same residue
EPHB3 c.1748+4C>T Benign ★★ same type
EPHB3 p.Phe689= Benign ★★ same type
EPHB3 p.Pro438= Benign ★★ same type
EPHB3 p.Ala220Thr Uncertain significance ★ ⚠ same type
EPHB3 p.Ala229Val Uncertain significance ★ ⚠ same type
EPHB3 p.Ala315Thr Uncertain significance ★ ⚠ same type
EPHB3 p.Ala332Val 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/ephb3-p-arg326his (accessed [today's date]).

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