Is EPHB1 p.Met724Leu (c.2170A>T) pathogenic?

EPHB1 p.Met724Leu (c.2170A>T) is classified Uncertain significance in EPHB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.3291); Ultra-rare (popmax 0.0267%, amr).

How common is EPHB1 p.Met724Leu (c.2170A>T) in the general population?

EPHB1 p.Met724Leu (c.2170A>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about EPHB1 p.Met724Leu (c.2170A>T)?

AlphaMissense predicts likely benign (score 0.3291) — an in-silico prediction, not a clinical call.

EPHB1 p.Met724Leu

c.2170A>T · VCV4249890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3291 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3291	likely benign
REVEL	0.412	indeterminate
SaProt	LLR -11.97	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 463 kb · p 2.5e-12 · regional, not allelic
Overall
CADD	26.5	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 0.0267% Admixed American · 16/59,994 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00266% 43/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,750
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00195%	51,304

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: EPHB1
Protein: p.Met724Leu
Coding: c.2170A>T
MANE Select: NM_004441
Type: single nucleotide variant
Location: chr3:135201513 (GRCh38)
Gene constraint: LOEUF 0.441 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.95 · 8 PDB
Residue 724: an α-helix; the protein kinase domain

Full EPHB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHB1 p.Ile561= Benign ★★ same type
EPHB1 p.Phe552= Benign/Likely benign ★★ same type
EPHB1 p.Thr981= Benign ★★ same type
EPHB1 c.2347-1G>A Uncertain significance ★ same type
EPHB1 p.Ala12Ser Uncertain significance ★ ⚠ same type
EPHB1 p.Ala132Gly Uncertain significance ★ ⚠ same type
EPHB1 p.Ala182Thr Uncertain significance ★ ⚠ same type
EPHB1 p.Ala39Val 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/ephb1-p-met724leu (accessed [today's date]).

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