Is CYREN p.Lys149= (c.447A>G) pathogenic?

CYREN p.Lys149= (c.447A>G) is classified Benign in CYREN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-06). Common (popmax 7.19%, afr) — too common for a highly-penetrant pathogenic allele.

CYREN p.Lys149=

Q: How common is CYREN p.Lys149= (c.447A>G) in the general population?

CYREN p.Lys149= (c.447A>G) is common (popmax 7.19%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.447A>G · rs35119111 · VCV780721

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 7.19%, 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
Pangolin	Δ0.52	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.28	GERP -2, phastCons 0.36
Overall
CADD	2.523	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.19% African / African-American · 5,389/74,984 alleles

Filtering AF 7.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.96%

Overall 0.396% 6,348/1,602,620 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.19%	14
Remaining individualsnot grpmax-eligible	0.5%	200
Admixed American	0.495%	202
Middle Eastern	0.314%	319
Finnishnot grpmax-eligible	0.0813%	1,230
European (non-Finnish)	0.0227%	4,399
South Asian	0.0209%	4,791

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: CYREN
Protein: p.Lys149=
Coding: c.447A>G
MANE Select: NM_024033
dbSNP: rs35119111
Type: single nucleotide variant
Location: chr7:135166638 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.81 · 1 PDB

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

Similar variants

CYREN p.Asp112His Uncertain significance ★ ⚠ same type
TMEM140 p.Ala104Gly Uncertain significance ★ ⚠ same type
TMEM140 p.Ala153Pro Uncertain significance ★ ⚠ same type
TMEM140 p.Arg174Lys Uncertain significance ★ ⚠ same type
TMEM140 p.Arg5Lys Uncertain significance ★ ⚠ same type
TMEM140 p.Asp41Glu Uncertain significance ★ ⚠ same type
TMEM140 p.Gln105Glu Uncertain significance ★ ⚠ same type
TMEM140 p.Gln63Pro 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/cyren-p-lys149 (accessed [today's date]).

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