Is EEFSEC p.Lys175Asn (c.525G>C) pathogenic?

EEFSEC p.Lys175Asn (c.525G>C) is classified Uncertain significance in EEFSEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: ambiguous (0.4542); Very rare (popmax 0.00801%, afr).

How common is EEFSEC p.Lys175Asn (c.525G>C) in the general population?

EEFSEC p.Lys175Asn (c.525G>C) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about EEFSEC p.Lys175Asn (c.525G>C)?

AlphaMissense predicts ambiguous (score 0.4542) — an in-silico prediction, not a clinical call.

EEFSEC p.Lys175Asn

c.525G>C · VCV4016375

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4542	ambiguous
REVEL	0.127	moderately benign-leaning
SaProt	LLR -9.33	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 255 kb · p 0.039 · regional, not allelic
Overall
CADD	24.5	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 0.00801% African / African-American · 6/74,868 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000496% 8/1,613,890 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,478
South Asian	0.0011%	91,070
European (non-Finnish)	8.47e-05%	1,179,970

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: EEFSEC
Protein: p.Lys175Asn
Coding: c.525G>C
MANE Select: NM_021937
Type: single nucleotide variant
Location: chr3:128262128 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 175: the tr-type g domain; a β-strand

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

Similar variants

EEFSEC p.Arg285Gln Uncertain significance ★★ ⚠ same type
EEFSEC p.Arg424Gln Uncertain significance ★★ ⚠ same type
EEFSEC p.Phe463Leu Uncertain significance ★★ ⚠ same type
EEFSEC p.Ala435Val Benign ★★ same type
EEFSEC p.Phe581Cys Benign ★★ same type
EEFSEC p.Pro180= Benign ★★ same type
EEFSEC p.Asp390Ala Likely pathogenic ★ ⚠ same type
EEFSEC p.Glu514Ter Likely pathogenic ★ 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/eefsec-p-lys175asn (accessed [today's date]).

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