Is EDC3 p.Leu37Val (c.109C>G) pathogenic?

EDC3 p.Leu37Val (c.109C>G) is classified Conflicting classifications of pathogenicity in EDC3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-09). AlphaMissense: likely pathogenic (0.6585); Rare (popmax 0.16%, sas).

How common is EDC3 p.Leu37Val (c.109C>G) in the general population?

EDC3 p.Leu37Val (c.109C>G) is rare (popmax 0.16%, sas) (gnomAD).

What do computational predictors say about EDC3 p.Leu37Val (c.109C>G)?

AlphaMissense predicts likely pathogenic (score 0.6585) — an in-silico prediction, not a clinical call.

EDC3 p.Leu37Val

c.109C>G · rs139450223 · VCV737729

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6585 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.16%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6585	likely pathogenic
REVEL	0.47	indeterminate
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 2.2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 19 kb · p 0.0048 · regional, not allelic
Overall
CADD	26.5	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 0.16% South Asian · 146/91,086 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.131%

Overall 0.0694% 1,120/1,614,140 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.245%	407
South Asiangrpmax	0.16%	624
Middle Eastern	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0768%	1,302
European (non-Finnish)	0.0619%	1,617
Admixed American	0.0333%	3,001
African / African-American	0.0173%	5,773

Finnish 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: EDC3
Protein: p.Leu37Val
Coding: c.109C>G
MANE Select: NM_025083
dbSNP: rs139450223
Type: single nucleotide variant
Location: chr15:74675016 (GRCh38)
Gene constraint: LOEUF 0.656 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 77.04 · 6 PDB
Residue 37: the sm domain; a β-strand; the 'required for p-body targeting and interaction with dcp1a' region

Full EDC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDC3 p.Leu37= Likely benign ★ same residue
EDC3 p.Arg260Trp Uncertain significance ★★ ⚠ same type
EDC3 p.Thr273= Benign ★★ same type
EDC3 c.821-2A>C Uncertain significance ★ same type
EDC3 p.Ala129Thr Uncertain significance ★ ⚠ same type
EDC3 p.Ala172Pro Uncertain significance ★ ⚠ same type
EDC3 p.Ala312Thr Uncertain significance ★ ⚠ same type
EDC3 p.Arg232His 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/edc3-p-leu37val (accessed [today's date]).

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