Is ERF p.Ser327= (c.981C>T) pathogenic?

ERF p.Ser327= (c.981C>T) is classified Benign in ERF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 18%, sas) — too common for a highly-penetrant pathogenic allele; Associated with TWIST1-related craniosynostosis.

What condition is associated with ERF p.Ser327= (c.981C>T)?

ERF p.Ser327= (c.981C>T) is associated with TWIST1-related craniosynostosis (ClinVar).

ERF p.Ser327=

Q: How common is ERF p.Ser327= (c.981C>T) in the general population?

ERF p.Ser327= (c.981C>T) is common (popmax 18%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.981C>T · rs61735151 · VCV1169686

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 18%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

TWIST1-related craniosynostosis

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 0.56	GERP -1, phastCons 0.99
Overall
CADD	6.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18% South Asian · 16,384/91,082 alleles

Filtering AF 17.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.7%

Overall 7.31% 117,982/1,613,790 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	18%	6
Middle Eastern	17.9%	6
Admixed American	11.7%	9
Ashkenazi Jewishnot grpmax-eligible	8.72%	11
Remaining individualsnot grpmax-eligible	8.02%	12
East Asian	7.25%	14
European (non-Finnish)	6.7%	15
Finnishnot grpmax-eligible	4.02%	25
African / African-American	1.41%	71
Amishnot grpmax-eligible	1.1%	91

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: ERF
Protein: p.Ser327=
Coding: c.981C>T
MANE Select: NM_006494
dbSNP: rs61735151
Type: single nucleotide variant
Location: chr19:42249131 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 327: a modified residue (phosphoserine)

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

Disease context

TWIST1-related craniosynostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERF p.Arg183Ter Pathogenic ★★ same condition
ERF p.Arg207Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Arg218Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Arg86Cys Pathogenic/Likely pathogenic ★★ same condition
ERF p.Ser24Ter Pathogenic/Likely pathogenic ★★ same condition
ERF p.Arg458Gly Uncertain significance ★★ ⚠ same condition
ERF p.Arg493His Uncertain significance ★★ ⚠ same condition
ERF p.Lys401Glu Uncertain significance ★★ ⚠ same condition

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/erf-p-ser327 (accessed [today's date]).

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