Is ERC1 p.Arg816Gln (c.2447G>A) pathogenic?

ERC1 p.Arg816Gln (c.2447G>A) is classified Uncertain significance in ERC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-30). AlphaMissense: likely benign (0.1119); Very rare (popmax 0.00445%, eas).

How common is ERC1 p.Arg816Gln (c.2447G>A) in the general population?

ERC1 p.Arg816Gln (c.2447G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about ERC1 p.Arg816Gln (c.2447G>A)?

AlphaMissense predicts likely benign (score 0.1119) — an in-silico prediction, not a clinical call.

ERC1 p.Arg816Gln

c.2447G>A · rs376405419 · VCV3090086

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1119	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -6.14	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 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 462 kb · p 5.7e-05 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,898 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00167% 27/1,613,988 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,449
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00169%	58,999
Admixed American	0.00167%	59,982
African / African-American	0.00133%	74,934
South Asian	0.0011%	91,082

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: ERC1
Protein: p.Arg816Gln
Coding: c.2447G>A
MANE Select: NM_178040
dbSNP: rs376405419
Type: single nucleotide variant
Location: chr12:1236864 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 75.64
Residue 816: the 'disordered' region

Full ERC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERC1 p.Ser393= Benign ★★ same type
ERC1 c.3214-1G>A Uncertain significance ★ same type
ERC1 p.Ala1058Val Uncertain significance ★ ⚠ same type
ERC1 p.Ala199Thr Uncertain significance ★ ⚠ same type
ERC1 p.Ala260Glu Uncertain significance ★ ⚠ same type
ERC1 p.Ala5Ser Uncertain significance ★ ⚠ same type
ERC1 p.Ala621Thr Uncertain significance ★ ⚠ same type
ERC1 p.Ala682Ser 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/erc1-p-arg816gln (accessed [today's date]).

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