Is EPHB3 p.Arg401Gln (c.1202G>A) pathogenic?

EPHB3 p.Arg401Gln (c.1202G>A) is classified Uncertain significance in EPHB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.1548); Ultra-rare (popmax 0.0174%, nfe).

How common is EPHB3 p.Arg401Gln (c.1202G>A) in the general population?

EPHB3 p.Arg401Gln (c.1202G>A) is ultra-rare (popmax 0.0174%, nfe) (gnomAD).

What do computational predictors say about EPHB3 p.Arg401Gln (c.1202G>A)?

AlphaMissense predicts likely benign (score 0.1548) — an in-silico prediction, not a clinical call.

EPHB3 p.Arg401Gln

c.1202G>A · VCV4018774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1548 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1548	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, 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 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 0.0174% European (non-Finnish) · 205/1,180,012 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.0147% 237/1,613,836 alleles · ultra-rare exomes 219/1,461,610 · genomes 18/152,226 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.024%	4,165
European (non-Finnish)grpmax	0.0174%	5,756
African / African-American	0.00801%	12,488
South Asian	0.00768%	13,013
Finnishnot grpmax-eligible	0.00627%	15,955

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: EPHB3
Protein: p.Arg401Gln
Coding: c.1202G>A
MANE Select: NM_004443
Type: single nucleotide variant
Location: chr3:184577031 (GRCh38)
Gene constraint: LOEUF 0.435 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.62 · 4 PDB
Residue 401: the fibronectin type-iii 1 domain

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

Similar variants

EPHB3 p.Arg401Trp 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-arg401gln (accessed [today's date]).

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