Is TKFC p.Ala334Gly (c.1001C>G) pathogenic?

TKFC p.Ala334Gly (c.1001C>G) is classified Benign in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). AlphaMissense: likely benign (0.1107); Common (popmax 12.6%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about TKFC p.Ala334Gly (c.1001C>G)?

AlphaMissense predicts likely benign (score 0.1107) — an in-silico prediction, not a clinical call.

TKFC p.Ala334Gly

Q: How common is TKFC p.Ala334Gly (c.1001C>G) in the general population?

TKFC p.Ala334Gly (c.1001C>G) is common (popmax 12.6%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1001C>G · VCV3910881

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1107 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.6%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1107	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.064	GERP -2.5
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	14.07	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 12.6% European (non-Finnish) · 148,951/1,179,668 alleles

Filtering AF 12.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.6%

Overall 10.6% 171,383/1,609,760 alleles · common exomes 159,305/1,457,458 · genomes 12,078/152,302 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	12.6%	8
Ashkenazi Jewishnot grpmax-eligible	9.27%	11
Remaining individualsnot grpmax-eligible	9.24%	11
Finnishnot grpmax-eligible	9.11%	11
Amishnot grpmax-eligible	8.57%	12
Admixed American	7.45%	13
Middle Eastern	7.34%	14
South Asian	2.21%	45
African / African-American	1.9%	53
East Asian	0.0334%	2,992

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: TKFC
Protein: p.Ala334Gly
Coding: c.1001C>G
MANE Select: NM_015533
Type: single nucleotide variant
Location: chr11:61343874 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 334: the dhak domain; a UniProt-annotated variant site (in)

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

Similar variants

TKFC p.Arg543Ile Likely pathogenic ★★ same type
TKFC p.Arg228Gln Uncertain significance ★★ ⚠ same type
TKFC p.Asp403Asn Uncertain significance ★★ ⚠ same type
TKFC p.Gln257Pro Uncertain significance ★★ ⚠ same type
TKFC c.194-13C>T Benign ★★ same type
TKFC c.775+39A>C Benign ★★ same type
TKFC p.Ala185Thr Benign ★★ same type
TKFC p.Thr157= Benign ★★ 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/tkfc-p-ala334gly (accessed [today's date]).

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