Is ERC2 p.Arg203Trp (c.607C>T) pathogenic?

ERC2 p.Arg203Trp (c.607C>T) is classified Uncertain significance in ERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: likely pathogenic (0.6964); Ultra-rare (popmax 0.0165%, mid).

How common is ERC2 p.Arg203Trp (c.607C>T) in the general population?

ERC2 p.Arg203Trp (c.607C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ERC2 p.Arg203Trp (c.607C>T)?

AlphaMissense predicts likely pathogenic (score 0.6964) — an in-silico prediction, not a clinical call.

ERC2 p.Arg203Trp

c.607C>T · VCV3845743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6964 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6964	likely pathogenic
REVEL	0.435	indeterminate
SaProt	LLR -11.62	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.94, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 139 kb · p 0.13 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000682% 11/1,613,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.00267%	37,510
East Asian	0.00223%	44,884
Admixed American	0.00167%	60,022
Remaining individualsnot grpmax-eligible	0.0016%	62,488
South Asian	0.0011%	91,060
European (non-Finnish)	0.000339%	294,969

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: ERC2
Protein: p.Arg203Trp
Coding: c.607C>T
MANE Select: NM_015576
Type: single nucleotide variant
Location: chr3:56434401 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 74.26

Full ERC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERC2 p.Ala105Ser Uncertain significance ★ ⚠ same type
ERC2 p.Ala107Thr Uncertain significance ★ ⚠ same type
ERC2 p.Ala202Val Uncertain significance ★ ⚠ same type
ERC2 p.Ala251Val Uncertain significance ★ ⚠ same type
ERC2 p.Ala333Ser Uncertain significance ★ ⚠ same type
ERC2 p.Ala371Pro Uncertain significance ★ ⚠ same type
ERC2 p.Ala724Thr Uncertain significance ★ ⚠ same type
ERC2 p.Ala835Thr 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/erc2-p-arg203trp (accessed [today's date]).

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