Is EPHB1 p.Ala547Val (c.1640C>T) pathogenic?

EPHB1 p.Ala547Val (c.1640C>T) is classified Uncertain significance in EPHB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.3332); Very rare (popmax 0.00223%, eas).

How common is EPHB1 p.Ala547Val (c.1640C>T) in the general population?

EPHB1 p.Ala547Val (c.1640C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about EPHB1 p.Ala547Val (c.1640C>T)?

AlphaMissense predicts likely benign (score 0.3332) — an in-silico prediction, not a clinical call.

EPHB1 p.Ala547Val

c.1640C>T · VCV4249900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3332 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3332	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -5.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 463 kb · p 2.5e-12 · regional, not allelic
Overall
CADD	22.9	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 0.00223% East Asian · 1/44,892 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000867% 14/1,613,836 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asiangrpmax	0.00223%	44,892
Remaining individualsnot grpmax-eligible	0.0016%	62,460
Finnishnot grpmax-eligible	0.00156%	64,008
European (non-Finnish)	0.000848%	117,987

Ashkenazi Jewish 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: EPHB1
Protein: p.Ala547Val
Coding: c.1640C>T
MANE Select: NM_004441
Type: single nucleotide variant
Location: chr3:135166022 (GRCh38)
Gene constraint: LOEUF 0.441 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.95 · 8 PDB

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-ala547val (accessed [today's date]).

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