Is EFNA3 p.Ser133= (c.399T>G) pathogenic?

EFNA3 p.Ser133= (c.399T>G) is classified Benign in EFNA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Common (popmax 8.06%, afr) — too common for a highly-penetrant pathogenic allele.

EFNA3 p.Ser133=

Q: How common is EFNA3 p.Ser133= (c.399T>G) in the general population?

EFNA3 p.Ser133= (c.399T>G) is common (popmax 8.06%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.399T>G · rs77832800 · VCV775143

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 8.06%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP -3.7, phastCons 0.99
Overall
CADD	11.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.06% African / African-American · 6,042/74,992 alleles

Filtering AF 7.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.82%

Overall 0.437% 7,051/1,612,022 alleles · common exomes 3,532/1,459,676 · genomes 3,519/152,346 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.06%	12
Remaining individualsnot grpmax-eligible	0.561%	178
Admixed American	0.465%	215
Ashkenazi Jewishnot grpmax-eligible	0.43%	232
Middle Eastern	0.413%	242
South Asian	0.0198%	5,049
European (non-Finnish)	0.0177%	5,641
Finnishnot grpmax-eligible	0.00314%	31,824

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: EFNA3
Protein: p.Ser133=
Coding: c.399T>G
MANE Select: NM_004952
dbSNP: rs77832800
Type: single nucleotide variant
Location: chr1:155085361 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.84
Residue 133: the ephrin rbd domain

Full EFNA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFNA3 p.Ala101Ser Uncertain significance ★ ⚠ same type
EFNA3 p.Ala168Val Uncertain significance ★ ⚠ same type
EFNA3 p.Arg219Gln Uncertain significance ★ ⚠ same type
EFNA3 p.Arg219Trp Uncertain significance ★ ⚠ same type
EFNA3 p.Arg45Trp Uncertain significance ★ ⚠ same type
EFNA3 p.Asn193Asp Uncertain significance ★ ⚠ same type
EFNA3 p.Asp57Glu Uncertain significance ★ ⚠ same type
EFNA3 p.Gln204Glu 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/efna3-p-ser133 (accessed [today's date]).

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