Is SEC61A1 p.Phe258= (c.774C>T) pathogenic?

SEC61A1 p.Phe258= (c.774C>T) is classified Likely benign in SEC61A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0538%, nfe).

How common is SEC61A1 p.Phe258= (c.774C>T) in the general population?

SEC61A1 p.Phe258= (c.774C>T) is ultra-rare (popmax 0.0538%, nfe) (gnomAD).

SEC61A1 p.Phe258=

c.774C>T · rs370619568 · VCV1095005

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0538%, nfe)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.193	benign-leaning
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.011	GERP -5.6, phastCons 0.83
Overall
CADD	10.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0538% European (non-Finnish) · 635/1,180,032 alleles

Filtering AF 0.0503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0489%

Overall 0.0413% 667/1,614,110 alleles · ultra-rare exomes 647/1,461,874 · genomes 20/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0538%	1,858
Remaining individualsnot grpmax-eligible	0.0432%	2,314
African / African-American	0.00534%	18,735
Admixed American	0.00167%	60,014

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: SEC61A1
Protein: p.Phe258=
Coding: c.774C>T
MANE Select: NM_013336
dbSNP: rs370619568
Type: single nucleotide variant
Location: chr3:128065034 (GRCh38)

Full SEC61A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/sec61a1-p-phe258 (accessed [today's date]).

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