Is KLC2 p.Pro517Ser (c.1549C>T) pathogenic?

KLC2 p.Pro517Ser (c.1549C>T) is classified Benign in KLC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0649); Common (popmax 25.1%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about KLC2 p.Pro517Ser (c.1549C>T)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

KLC2 p.Pro517Ser

Q: How common is KLC2 p.Pro517Ser (c.1549C>T) in the general population?

KLC2 p.Pro517Ser (c.1549C>T) is common (popmax 25.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1549C>T · rs2276036 · VCV1598796

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 25.1%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -4.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.073	GERP -2.3
Regional constraint	o/e 0.73	unconstrained · MANE · 8,358 bp · p 1.4e-14 · regional, not allelic
Overall
CADD	3.72	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 25.1% East Asian · 11,188/44,582 alleles

Filtering AF 24.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.5%

Overall 17.1% 274,586/1,601,804 alleles · common exomes 247,642/1,449,594 · genomes 26,944/152,210 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	25.1%	4
Ashkenazi Jewishnot grpmax-eligible	21.3%	5
Middle Eastern	19.9%	5
African / African-American	18.4%	5
Remaining individualsnot grpmax-eligible	17.7%	6
Finnishnot grpmax-eligible	17.6%	6
European (non-Finnish)	16.9%	6
South Asian	16.3%	6
Amishnot grpmax-eligible	12.7%	8
Admixed American	12.7%	8

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: KLC2
Protein: p.Pro517Ser
Coding: c.1549C>T
MANE Select: NM_001318734
dbSNP: rs2276036
Type: single nucleotide variant
Location: chr11:66265959 (GRCh38)
Gene constraint: LOEUF 0.616 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.79 · 2 PDB
Residue 517: a UniProt-annotated variant site (in); the 'disordered' region

Full KLC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KLC2 p.Arg110His Uncertain significance ★★ ⚠ same type
KLC2 p.Arg418Gln Uncertain significance ★★ ⚠ same type
KLC2 p.Arg418Trp Uncertain significance ★★ ⚠ same type
KLC2 p.Arg479His Uncertain significance ★★ ⚠ same type
KLC2 p.Arg509Gln Uncertain significance ★★ ⚠ same type
KLC2 p.Arg616Gln Uncertain significance ★★ ⚠ same type
KLC2 p.Arg96Gln Uncertain significance ★★ same type
KLC2 p.Asn170Ser 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/klc2-p-pro517ser (accessed [today's date]).

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