Is ELP4 p.Ser321Pro (c.961T>C) pathogenic?

ELP4 p.Ser321Pro (c.961T>C) is classified Uncertain significance in ELP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: likely pathogenic (0.8732); Ultra-rare (popmax 0.0217%, amr).

How common is ELP4 p.Ser321Pro (c.961T>C) in the general population?

ELP4 p.Ser321Pro (c.961T>C) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about ELP4 p.Ser321Pro (c.961T>C)?

AlphaMissense predicts likely pathogenic (score 0.8732) — an in-silico prediction, not a clinical call.

ELP4 p.Ser321Pro

c.961T>C · VCV3645063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8732	likely pathogenic · top 6% in ELP4
REVEL	0.402	indeterminate
SaProt	LLR -11.26	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 3.5	GERP 0.21, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 274 kb · p 0.85 · regional, not allelic
Overall
CADD	23.3	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 0.0217% Admixed American · 13/59,776 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.000808% 13/1,609,574 alleles · ultra-rare exomes 12/1,457,858 · genomes 1/151,716 · joint denominator

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: ELP4
Protein: p.Ser321Pro
Coding: c.961T>C
MANE Select: NM_019040
Type: single nucleotide variant
Location: chr11:31647774 (GRCh38)
Gene constraint: LOEUF 1.377 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49

Full ELP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PAX6 p.Arg222Trp Pathogenic/Likely pathogenic ★★ same type
PAX6 p.Ter437Gln Pathogenic/Likely pathogenic ★★ same type
PAX6 p.Ter437Leu Pathogenic/Likely pathogenic ★★ same type
ELP4 p.Arg163His Uncertain significance ★★ ⚠ same type
ELP4 p.Arg31Ser Uncertain significance ★★ ⚠ same type
ELP4 p.Arg395His Uncertain significance ★★ same type
ELP4 p.Asn244Ser Uncertain significance ★★ ⚠ same type
ELP4 p.Gln165Pro 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/elp4-p-ser321pro (accessed [today's date]).

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