Is EMC4 p.Pro171His (c.512C>A) pathogenic?

EMC4 p.Pro171His (c.512C>A) is classified Uncertain significance in EMC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-22). AlphaMissense: likely pathogenic (0.617); Absent from gnomAD v4.1.

How common is EMC4 p.Pro171His (c.512C>A) in the general population?

EMC4 p.Pro171His (c.512C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EMC4 p.Pro171His (c.512C>A)?

AlphaMissense predicts likely pathogenic (score 0.617) — an in-silico prediction, not a clinical call.

EMC4 p.Pro171His

c.512C>A · VCV3844596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.617 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.617	likely pathogenic
REVEL	0.258	benign-leaning
SaProt	LLR -11.47	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 4,670 bp · p 1.8e-05 · regional, not allelic
Overall
CADD	24.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EMC4
Protein: p.Pro171His
Coding: c.512C>A
MANE Select: NM_016454
Type: single nucleotide variant
Location: chr15:34228585 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 67.65 · 9 PDB
Residue 171: an α-helix

Full EMC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMC4 p.Ala3Val Uncertain significance ★ ⚠ same type
EMC4 p.Arg108Ter Uncertain significance ★ same type
EMC4 p.Arg68His Uncertain significance ★ ⚠ same type
EMC4 p.Gly35Asp Uncertain significance ★ ⚠ same type
EMC4 p.Ile116Phe Uncertain significance ★ ⚠ same type
EMC4 p.Ile19Thr Uncertain significance ★ ⚠ same type
EMC4 p.Lys129Asn Uncertain significance ★ ⚠ same type
EMC4 p.Phe85Leu 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/emc4-p-pro171his (accessed [today's date]).

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