Is EFNB2 p.Ser268Leu (c.803C>T) pathogenic?

EFNB2 p.Ser268Leu (c.803C>T) is classified Uncertain significance in EFNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: ambiguous (0.471); Very rare (popmax 0.00266%, afr).

How common is EFNB2 p.Ser268Leu (c.803C>T) in the general population?

EFNB2 p.Ser268Leu (c.803C>T) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about EFNB2 p.Ser268Leu (c.803C>T)?

AlphaMissense predicts ambiguous (score 0.471) — an in-silico prediction, not a clinical call.

EFNB2 p.Ser268Leu

c.803C>T · VCV4663319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.471 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.471	ambiguous
REVEL	0.742	pathogenic-leaning
SaProt	LLR -9.76	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,723 bp · p 2.4e-05 · regional, not allelic
Overall
CADD	29.8	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 0.00266% African / African-American · 2/75,050 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000205% 3/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,525
European (non-Finnish)	8.47e-05%	1,180,034

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: EFNB2
Protein: p.Ser268Leu
Coding: c.803C>T
MANE Select: NM_004093
Type: single nucleotide variant
Location: chr13:106493239 (GRCh38)
Gene constraint: LOEUF 0.261 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.60 · 10 PDB

Full EFNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFNB2 p.Tyr73Ter Likely pathogenic ★ same type
EFNB2 p.Ala157Thr Uncertain significance ★ ⚠ same type
EFNB2 p.Ala296Ser Uncertain significance ★ ⚠ same type
EFNB2 p.Arg156Lys Uncertain significance ★ ⚠ same type
EFNB2 p.Arg182His Uncertain significance ★ ⚠ same type
EFNB2 p.Arg253Gln Uncertain significance ★ ⚠ same type
EFNB2 p.Arg253Trp Uncertain significance ★ ⚠ same type
EFNB2 p.Arg277Cys 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/efnb2-p-ser268leu (accessed [today's date]).

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