Is ERF p.Ser137Leu (c.410C>T) pathogenic?

ERF p.Ser137Leu (c.410C>T) is classified Uncertain significance in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-26). AlphaMissense: ambiguous (0.3414); Very rare (popmax 0.00563%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERF p.Ser137Leu (c.410C>T)?

ERF p.Ser137Leu (c.410C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ERF p.Ser137Leu (c.410C>T) in the general population?

ERF p.Ser137Leu (c.410C>T) is very rare (popmax 0.00563%, nfe) (gnomAD).

What do computational predictors say about ERF p.Ser137Leu (c.410C>T)?

AlphaMissense predicts ambiguous (score 0.3414) — an in-silico prediction, not a clinical call.

ERF p.Ser137Leu

c.410C>T · VCV4250660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3414 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00563%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3414	ambiguous
REVEL	0.072	moderately benign-leaning
SaProt	LLR -7.09	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.22 · evaluated, not missing
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	24.0	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 0.00563% European (non-Finnish) · 66/1,171,464 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00414%

Overall 0.00437% 70/1,600,014 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00563%	17,749
East Asian	0.00224%	44,726
Admixed American	0.00169%	59,330
Remaining individualsnot grpmax-eligible	0.00161%	61,922
African / African-American	0.00134%	74,706

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.Ser137Leu
Coding: c.410C>T
MANE Select: NM_006494
Type: single nucleotide variant
Location: chr19:42249702 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 137: the 'disordered' region

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.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
ERF p.Val128Gly 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-ser137leu (accessed [today's date]).

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