Is ERF p.Thr273Ser (c.818C>G) pathogenic?

ERF p.Thr273Ser (c.818C>G) is classified Likely benign in ERF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-14). AlphaMissense: likely benign (0.0616); Ultra-rare (popmax 0.0667%, mid); Associated with Inborn genetic diseases.

What condition is associated with ERF p.Thr273Ser (c.818C>G)?

ERF p.Thr273Ser (c.818C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ERF p.Thr273Ser (c.818C>G) in the general population?

ERF p.Thr273Ser (c.818C>G) is ultra-rare (popmax 0.0667%, mid) (gnomAD).

What do computational predictors say about ERF p.Thr273Ser (c.818C>G)?

AlphaMissense predicts likely benign (score 0.0616) — an in-silico prediction, not a clinical call.

ERF p.Thr273Ser

c.818C>G · rs374191725 · VCV3090148

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0616 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0616	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -5.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,421 bp · p 0.024 · regional, not allelic
Overall
CADD	21.7	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 0.0667% Middle Eastern · 4/6,000 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00911% 146/1,602,550 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.205%	489
Middle Easterngrpmax	0.0667%	1,500
Remaining individualsnot grpmax-eligible	0.021%	4,769
African / African-American	0.0107%	9,363
European (non-Finnish)	0.00519%	19,256

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr273Ser
Coding: c.818C>G
MANE Select: NM_006494
dbSNP: rs374191725
Type: single nucleotide variant
Location: chr19:42249294 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERF p.Thr273= Likely benign ★ same residue
ERF p.Gln263Ter Pathogenic ★★ same condition
ERF p.Ala462Pro Uncertain significance ★★ ⚠ same condition
ERF p.Arg179His Uncertain significance ★★ ⚠ same condition
ERF p.Arg233Gln Uncertain significance ★★ ⚠ same condition
ERF p.Arg312Gln Uncertain significance ★★ ⚠ same condition
ERF p.Arg546Ter 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-thr273ser (accessed [today's date]).

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