Is SELE p.Glu421Gln (c.1261G>C) pathogenic?

SELE p.Glu421Gln (c.1261G>C) is classified Benign in SELE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0782); Low-frequency (popmax 4.52%, afr).

How common is SELE p.Glu421Gln (c.1261G>C) in the general population?

SELE p.Glu421Gln (c.1261G>C) is low-frequency (popmax 4.52%, afr) (gnomAD).

What do computational predictors say about SELE p.Glu421Gln (c.1261G>C)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

SELE p.Glu421Gln

c.1261G>C · rs5366 · VCV789698

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.52%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1	GERP -3.4
Regional constraint	o/e 1.03	unconstrained · MANE · 7,865 bp · p 0.43 · regional, not allelic
Overall
CADD	0.176	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 4.52% African / African-American · 3,388/74,894 alleles

Filtering AF 4.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.34%

Overall 0.241% 3,883/1,612,824 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.52%	22
Remaining individualsnot grpmax-eligible	0.36%	278
Admixed American	0.345%	290
Middle Eastern	0.132%	756
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,217
South Asian	0.0198%	5,041
European (non-Finnish)	0.00263%	38,055

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: SELE
Protein: p.Glu421Gln
Coding: c.1261G>C
MANE Select: NM_000450
dbSNP: rs5366
Type: single nucleotide variant
Location: chr1:169728076 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.28 · 17 PDB
Residue 421: the sushi 4 domain; a disulfide bond; a UniProt-annotated variant site (in)

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

Similar variants

SELE p.Glu277Lys Uncertain significance ★★ ⚠ same type
SELE p.Phe325Leu Uncertain significance ★★ ⚠ same type
SELE p.Asn291= Benign ★★ same type
SELE p.Asn420= Benign ★★ same type
SELE p.Glu295Lys Benign ★★ same type
SELE p.Leu575Phe Benign ★★ same type
SELE c.901+9G>T Uncertain significance ★ same type
SELE p.Ala249Ser 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/sele-p-glu421gln (accessed [today's date]).

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