Is CREM p.Lys104= (c.312G>A) pathogenic?

CREM p.Lys104= (c.312G>A) is classified Benign in CREM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Common (popmax 10.8%, afr) — too common for a highly-penetrant pathogenic allele.

CREM p.Lys104=

Q: How common is CREM p.Lys104= (c.312G>A) in the general population?

CREM p.Lys104= (c.312G>A) is common (popmax 10.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.312G>A · rs11010115 · VCV776507

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 10.8%, 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 4.5	phastCons 1
Overall
CADD	8.899	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.8% African / African-American · 8,092/74,990 alleles

Filtering AF 10.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.5%

Overall 0.6% 9,685/1,613,922 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.8%	9
Middle Eastern	0.908%	110
Remaining individualsnot grpmax-eligible	0.728%	137
Admixed American	0.595%	168
European (non-Finnish)	0.0578%	1,730
Ashkenazi Jewishnot grpmax-eligible	0.0474%	2,112
South Asian	0.0308%	3,252
East Asian	0.00223%	44,870
Finnishnot grpmax-eligible	0.00156%	64,034

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: CREM
Protein: p.Lys104=
Coding: c.312G>A
MANE Select: NM_183011
dbSNP: rs11010115
Type: single nucleotide variant
Location: chr10:35179179 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 61.54
Residue 104: the kid domain

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

Similar variants

CREM p.Arg244= Benign ★★ same type
CREM p.Ser226Leu Likely benign ★★ same type
CREM c.*344A>G Uncertain significance ★ ⚠ same type
CREM c.*354A>G Uncertain significance ★ ⚠ same type
CREM c.*368C>A Uncertain significance ★ ⚠ same type
CREM p.Ala168Val Uncertain significance ★ ⚠ same type
CREM p.Ala58Ser Uncertain significance ★ ⚠ same type
CREM p.Arg211Gln 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/crem-p-lys104 (accessed [today's date]).

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